TW201705959A - Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on BTK occupancy and BTK resynthesis rate - Google Patents

Abstract

In an embodiment, therapeutic methods and uses of Bruton's Tyrosine Kinase (BTK) inhibitors for treatment of cancer, inflammation, immune disorders, and autoimmune disorders, including dermatoses, and for transplantation prophylaxis, based on BTK occupancies and/or BTK resynthesis rates for B cells in various diseases, tissue compartments, including bone marrow and lymph nodes, are described. In an embodiment, dosing regimens for a BTK inhibitor for treatment of cancer, inflammation, immune disorders, and autoimmune disorders, including dermatoses, and for transplantation prophylaxis, based on BTK occupancies and/or BTK resynthesis rates for B cells in various diseases, tissue compartments, including bone marrow and lymph nodes, are described.

Description

Method for treating cancer, immune and autoimmune diseases and inflammatory diseases based on Bruton's tyrosine kinase (BTK) occupancy and BTK resynthesis rate Cross-reference to related applications

The present application claims the benefit of the International Patent Application No. PCT/IB2015/056038, filed on Aug. 7, 2015, and the entire disclosure of for reference.

The present invention discloses lymphoma, leukemia, solid tumor, immune and autoimmune diseases based on the BTK occupation and/or resynthesis rate in cells and tissue chambers treated with Bruton's tyrosine kinase (BTK) inhibitor. And therapeutic compositions and uses of inflammatory diseases.

Bruton's tyrosine kinase (BTK) is a Tec family of non-receptor protein kinases expressed in B cells and bone marrow cells. The function of BTK in the signaling pathway by activating B cell receptor (BCR) and FCεR1 on mast cell B has been fully established. BTK is a key enzyme in BCR activation and plays an important role in B cell maturation in bone marrow and lymphoid tissues. The antigen encounters the selection of high affinity cell lines, immunoglobulin class switching and antibody-producing plasma cell development. Mutations in BTK function in humans lead to primary immunodeficiency disease (X-linked gamma globulinemia, XLA), characterized by a block between the pro (pro) and pre (pre) B cell phases. Cell development defects. The result is almost no B lymphocytes, resulting in a significant reduction in all types of serum immunoglobulins. In addition, the bonding of BCR is induced by BTK and its downstream quality PLC. 2 Communications, which activates the transcription factor NFκB necessary for the development of innate and strained immune responses. In B lymphocytes, NFκB up-regulates the expression of pro-survival factors, which support B cell line proliferation and decrease B cell line apoptosis. In BCR-stimulated autoreactive or malignant B cell lines, BTK signaling can lead to undue growth or survival of disease-induced B cells, resulting in autoantibody production, inflammation, lymphadenopathy, and reactive hematocytopenia. In mice with spontaneously mutated BTK, constitutive activation or inactivation of BTK signaling activity causes severe immunodeficiency disease, indicating a strict developmental control of BTK expression and communication in B cells to properly adjust strainability Immune function is necessary. In addition to the BCR signal, BTK also activates in response to signals that cause autoimmune B cells (such as TLR9, a receptor for nucleic acids) and inflammatory processes that cause structural damage that causes autoimmune diseases, such as Fc ε R1 in mast cells and RANKL in osteoclasts. These findings support the key role of BTK in regulating the production of autoantibodies and inflammation of autoimmune diseases.

Regulation of BTK expression levels during B cell development and activation is tightly controlled; BTK levels are higher in hematopoietic and pre- and pro-B cell stages. The resting B lymphocytes in the surrounding tissue have a lower BTK than observed in the bone marrow. Stimulation of BCR results in rapid BTK performance induction, increasing protein content by a factor of 10 within a few hours of stimulation, as described in (Nisitani et al., PNAS. 2000, 97, 2737-2742). In addition to the post-translational mechanisms that occur rapidly after BCR stimulation, BTK expression in B cells also results from transcriptional activation by NFKB-mediated (Yu et al., Blood, 2008, 111(9), 4617-4626). Because BTK signaling induces NFκB, there is a positive feedback loop in activated B cells. These findings indicate that inhibition of BTK affects both downstream results of BCR engagement (such as production of antibodies) and inhibition of the performance of BTK itself, which may further modulate the reactivity of autoimmune B cells.

Other diseases in which dysfunctional B cells play an important role are B cell malignant diseases. The reported role of BTK in BCR communication and in the regulation of B cell proliferation and apoptosis indicates the possibility of treating B cell lymphoma with BTK inhibitors. Therefore, the development of BTK inhibitors has become a possible treatment, as in: Cruz et al., OncoTargets & Therapy 2013, 6, 161-176; Hendriks et al., Nat. Rev. Cancer, 2014, 14, 219-232; Byrd et al. .J. Med. 2013, 369, 32-42.

B cells are a key component of the strained immune system. B cells in adults initially develop from hematopoietic stem cells in the bone marrow and mature in the bone marrow along with their developmental stages into pro-B cells characterized by the expression of cell surface proteins (primary B cells, pre-B cells, immature B cells and naïve B cells, as in Perez-Andres et al., Cytometry B (Clinical Cytometry), 2013, 78B (Suppl. 1), S47-S60 and Allman et al., Curr. Opin. Immunol. As described in 20, 149-157, B cells leaving the bone marrow can migrate to the spleen and secondary lymphoid organs and undergo additional development after antigen stimulation, which also results in the expression of cell surface proteins, characterizing the activation and development of B cells. And the development depends on the functional T helper cells. The shift of T cells depends in part on the antigenic system from the myeloid B cells or the professional antigen producing cells (APC) (such as trees). The subset of cells (eg, follicular dendritic cells, Langerhans cells) and the background of activated mononuclear spheres and/or macrophages appear. In fact, many bone marrow-derived cells also contain functional BTK. About promoting hair And the antigenic quality of these cells, as well as T cell fate (as a helper, inflammatory or inhibitory cell), depends on the activation and maturation status of APC, which can be affected by stimulation through the BTK pathway. Signal integration to direct the development of B cells from the bone marrow after migration in the surrounding chamber. After antigen stimulation occurs in the designated surrounding tissue chamber, the B cells can be further differentiated into subpopulations and can be recycled to different tissues, including mucosa. And BM, in which long-lived plasma cells produce antibodies and are recycled to inflamed sites, such as synovium in rheumatoid arthritis (RA) and osteoarthritis (OA) Tissue, brain parenchyma in multiple sclerosis (MS), exocrine glands in Sjogren's syndrome (SS), and pemphigus in large blisters, psoriasis vulgaris, systemic lupus erythematosus (SLE) and skin/connective tissue in scleroderma/systemic sclerosis.

The present invention includes the surprising discovery that the rate of BTK resynthesis and the rate of BTK regeneration in B cells after treatment with a covalent inhibitor of BTK in the human body differs between disease states and healthy individuals, and may There are also differences between individuals who are otherwise affected by the same disease symptoms.

The present invention includes the surprising discovery that BTK inhibition at a therapeutically relevant site in a mammal can be achieved by treatment with a low dose of a covalently inactivated BTK kinase, with low doses matching or exceeding the new BTK positive standard. The rate of synthesis of target cells or the interval of BTK resynthesis rates in existing and newly generated target cells is delivered.

In addition, the present invention encompasses the novel discovery that human treatment of BTK inhibitors that covalently inactivate BTK kinase directly impacts BTK resynthesis rate, causing BTK resynthesis rate to decrease upon complete inhibition and resulting in healthy volunteers The target BTK content is reduced for each of the target B cells and leukemia B cells of patients with chronic lymphocytic leukemia (CLL).

Among them, the most active room for BCR communication and the room with the fastest cell proliferation of immune cells have a higher rate of BTK resynthesis. The novelty of the present invention is due to the unexpected effect of BTK covalent inhibitors on the rate of BTK resynthesis and the close relationship between BTK resynthesis and BTK target occupancy. Because of the irreversible nature of the interaction of BTK kinases with covalent inhibitors, the pharmacokinetic/pharmacodynamic effects of BTK signaling inhibition are linked to the rate of recombination of BTK.

Impaired transmission through the BTK pathway may result in different effects on the BTK resynthesis rate depending on the extent of BTK inhibition. In humans, increased rates of BTK resynthesis are observed following treatment with BTK covalent inhibitors that result in lower levels of BTK target occupancy; conversely, appropriate doses to achieve higher levels of BTK inhibition A reduced rate of BTK resynthesis was observed after treatment. This novel result in the human body demonstrates the importance of achieving an appropriate degree of BTK inhibition in the tissue chamber of interest.

The present invention includes the discovery that a BTK target as measured in human peripheral blood treated with a covalently inactivated BTK kinase occupies a BTK target that is reflected in one or more tissue chambers other than the peripheral blood. The BTK target occupancy in the tissue chamber can also be accurately measured in a variety of ways. The rate of re-synthesis of BTK in a human or mammal treated with a covalently inactivated BTK kinase agent is directly proportional to the unoccupied BTK produced at the target site, as measured in the BTK target occupancy assay. The BTK resynthesis rate can be predicted using a computer model of the concentration-time profile of the data using BTK covalent inhibitors from the peripheral blood and tissue compartments and BTK targets. Prediction of BTK resynthesis in a chamber of interest can be used to identify a target dose and/or dosing schedule sufficient to be exposed to a BTK inhibitor to completely inhibit BTK in the chamber of interest and reduce during the dosing interval BTK resynthesis rate.

The present invention includes the surprising discovery that the dosing schedule can be adjusted to achieve the desired intensity of BTK inhibition, thereby maintaining functional inhibition of B cell receptor (BCR) signaling in the diseased tissue compartment of interest, without the need for oral administration. Plasma Cmax was increased after administration.

In addition, different chambers in the body have different rates of BTK resynthesis. In one embodiment, the method for treating a particular disease with a BTK inhibitor is directed to a resynthesis chamber that is most active in treating the disease, and the rate of resynthesis of the chamber is effective to formulate a drug delivery configuration for the BTK inhibitor.

In rheumatoid arthritis (RA) and osteoarthritis, the inflammatory environment of the diseased joint results in the development of lymphoid follicular structures in tissues with high proliferation rates and autoantigen-specific stimulation of B cell receptor signaling. At the site of an inflamed bone disease, osteoclasts stimulated by inflammatory factors (such as the nuclear factor kappa- beta ligand receptor activator (RANKL)) induce BTK signaling, resulting in activated phenotype and secretion of osteolytic enzymes. , further damage the bones in this room. Treatment of patients with RA or osteolytic bone disease with a covalent inhibitor of BTK kinase requires adequate delivery of the BTK inhibitor to the synovial fluid, the joint of the diseased joint or the bone. The method used involves inhibiting the transmission of BCR media by inhibiting BTK in such chambers to alleviate inflammation and progressive destruction of joints and bone tissue.

In lupus nephritis, cross-linking of autoreactive antibodies and deposition of immune complexes in the glomeruli of the kidney results in an inflammatory response that causes activation of endothelial cells and epithelial cells of the renal cortex, outside of the mononuclear sphere Infiltration and activation of tissue macrophages, supplementation of neutrophils and activated fibroblasts, and progressive loss of glomerular function. Systemic lupus erythematosus In (SLE), the development of autoantibodies occurs in tissue compartments where inappropriate survival of autoreactive B cell strains and autoreactive B cells mature into plasma cells occur after BCR stimulation. The method used comprises inhibiting BTK in a chamber that autoreactive B cell proliferation and/or producing autoantibodies and inhibiting BTK in a chamber associated with tissue inflammation such as kidney, connective tissue and skin.

In chronic lymphocytic leukemia (CLL) and small lymphoblastic lymphoma, BTK signaling via BCR signaling in tumorigenic B cells in the bone marrow drives tumor proliferation, induces anti-apoptotic proteins, and releases malignant cells to central blood. In the chamber and surrounding lymphoid tissues, such as lymph nodes and spleen, it becomes a site of swollen lymph nodes. In addition, CLL and small lymphoblastic lymphoma (SLL) cells may undergo further proliferation in the enlarged lymph nodes within such tissues, as evidenced by the presence of Ki67 (proliferation marker). Although the absolute number of lymphocytes (ALC) is monitored during CLL treatment, reactions in the swollen lymph nodes and in the bone marrow require penetration into the chambers with effective treatment.

In diffuse large B-cell lymphoma (DLBCL), the diversity of patients may have a rate of hyperplasia of lymph nodes or the presence of extranodal lesions. For example, a higher metabolic activity is observed by scanning a lymph node subpopulation of lymphomas in a patient with positron emission tomography (PET). The rate of proliferation of different lesions represents a different and renewed rate of BTK synthesis and can be considered as a separate chamber with a higher or lower rate of BTK resynthesis.

In DLBCL, the rate of proliferation of patient-to-patient diversity can be associated with specific mutations (such as p53 inactivation) among other invasive markers. The expression of the oncogene c-Myc correlates with the performance of anti-apoptotic proteins such as Bcl-2 or Bcl-6. The therapeutic dose and/or configuration of the different BTK inhibitors is identified in such patient subpopulations and other patients defined by the rate of proliferation or BTK resynthesis rate.

Hyperproliferative or invasive DLBCL reflects enhanced BCR signaling, as indicated in the B cell subpopulation of tumor-activated sputum, which facilitates rapid BTK resynthesis and dependence on BTK signaling pathways to spread Growth signal of BCR media.

In solid tumors, the matrix component often includes a variety of different tumor-associated lymphocytes and bone marrow cells, such as tumor-associated macrophages, which are capable of promoting angiogenesis and immunosuppressive effects within the tumor microenvironment. Such cells have the ability to alter the tropism of new infiltrating cells, the monitoring of malignant cells, and the phenotype and function of the immune media, or toward immunosuppressive phenotypes. Thus, regulatory B and T lymphocytes (Bregs and Tregs), bone marrow-derived suppressor cells (MDSCs), and tissue-inherent tissue cells, dendritic cells, and mast cells provide matrix support and reduce congenital and Strained immune surveillance. When a BTK inhibitor is used to treat solid tumors and hematological malignancies characterized by infiltration or stromal cells, the immunological component of the tumor microenvironment is therefore also the tissue compartment of interest for treatment.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a dose of Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide in the tissue chamber Target BTK occupied.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, wherein the target BTK occupancy is selected from the group consisting of: greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96% , greater than 97%, greater than 98%, and greater than 99%.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where BTK occupancy is estimated by the rate of BTK resynthesis in tumor lesions or disease sites.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of a BTK inhibitor during the second period, wherein the second dose is less than the first dose The amount is sufficient and sufficient to provide target BTK occupancy in the tissue compartment, wherein the BTK occupancy is estimated from a metabolically active profile or a proliferation index in the tumor lesion or disease site. In one embodiment, the metabolically active profile is measured using a method selected from the group consisting of magnetic resonance imaging and positron emission tomography.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where BTK occupancy is assessed based on the binding of BTK probes that bind unoccupied BTK in the lesion or disease site. In one embodiment, the BTK probe is selected from the group consisting of a fluorescent probe and a positron emission tomography probe.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where BTK occupancy is assessed based on the average BTK resynthesis rate of the patient population with the BTK vector.

In a preferred embodiment, the invention includes treating a human body A method of treating a condition of a BTK vector comprising the steps of: (a) administering a first dose of Bruton's tyrosine kinase (BTK) inhibitor sufficient to provide a target BTK occupancy in a tissue chamber during a first period And (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a target BTK occupancy in the tissue chamber, wherein the tissue chamber is selected from the group consisting of Group: peripheral blood B cells, bone marrow B cells, lymph node B cells, autoreactive B cells, plasma cells, regulatory B cells, follicular dendritic cells, dendritic cells derived from bone marrow, tumor stroma, and Tumor-associated macrophages, mast cells, alveolar macrophages, dust cells, plasmacytoid dendritic cells, epidermal lymphocyte antigen (CLA)-positive T cells, lymphoid cells, Langerhans cells, mononuclear cells, macrophages Cells, tissue cells, Kupffer cells, glial cells, microglia, Schwann cells, Ito cells, hepatic stellate cells, pancreatic stellate cells, glioma cells, malignant B cells, adipocytes, sarcoma cells, granules ball Neutrophil, eosinophil, hematopoietic stem cells, serous cells, mesenchymal cells, osteoblasts, osteoclasts, lymphocytes infiltrating immune cells and inflammatory exudate.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the tissue compartment is selected from the group consisting of: peripheral blood, bone marrow, germinal center, Lymphoid follicles, lymphoid tissues associated with intestinal tubes, tonsils, lymphoma lesions, ectopic lymphoid tissue, ectopic nodules, lymph node lesions, lymphadenopathy, spleen, solid tumors, tumor microenvironment, tumor stroma, bone, bone lesions , bone metastasis, synovial fluid, articular surface, joints, kidney, liver, lung, branch tubules / bronchioles, mediastinum, pleura, peritoneum, cystadenocarcinoma, heart, pancreas, sinusoids, eyes, nerves, brain, brain Metastasis, brain lesions, central nervous system, skin, stomach, lamina propria, intestinal tube, colon, exocrine gland, salivary gland, lacrimal gland, breast, dermis, subcutaneous tissue, epidermis, perivascular, inflammatory lesions, granuloma, mast cell tumor, Pimples, testicles, ovaries and bladder.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the BTK inhibitor is selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, which further comprises the step of determining the occupancy of the target BTK in the tissue chamber using a relative resynthesis rate.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where BTK inhibition The first dose of the agent is administered once a day.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the first dose of the BTK inhibitor is administered twice daily.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the first dose of the BTK inhibitor is administered three times a day.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a dose of Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide in the tissue chamber The target BTK is occupied, wherein the second dose of the BTK inhibitor is administered once a day.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the second dose of the BTK inhibitor is administered twice daily.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the second dose of the BTK inhibitor is administered three times a day.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where BTK inhibition The first dose of the agent is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the second dose of the BTK inhibitor is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the first period is selected from the group consisting of: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, and 21 days.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period Bruton's tyrosine kinase (BTK) inhibitor; and (b) in the second period The second dose of the BTK inhibitor is administered, wherein the second dose is less than the first dose and is sufficient to provide target BTK occupancy in the tissue chamber, wherein the second period is selected from the group consisting of: 2 weeks, 1 month , February, March, June, September, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years and 10 years.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the first dose of the BTK inhibitor is administered orally.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the first dose of the BTK inhibitor is administered topically.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of a BTK inhibitor during the second period, wherein the second dose is less than the first dose The amount is sufficient to provide the target BTK occupancy in the tissue chamber, wherein the second dose of the BTK inhibitor is administered orally.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK is occupied, wherein the second dose of the BTK inhibitor is administered topically.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the BTK-mediated disorder is a cancer selected from the group consisting of: Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphoblastic lymphoma Diffuse large B-cell lymphoma, mantle cell lymphoma, MALT lymphoma, Waldenström's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic leukemia, Burke Burkitt's leukemia, juvenile myelomonocytic leukemia, anterior lymphocytic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma Lung cancer Squamous cell carcinoma, skin Cancer, melanoma, eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, cervical cancer Correlation between cervical cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system cancer, acquired immunodeficiency syndrome Cancer, cervical carcinoma, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary exudative lymphoma, adenoid cystic carcinoma, hepatocellular carcinoma, T-cell leukemia, and mastocytosis .

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the BTK-mediated disorder is an inflammatory, immunological or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, osteoarthritis , osteoporosis, atherosclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema and scleroderma), systemic sclerosis, diabetes, diabetic retinopathy, premature retinopathy, age-related macular Degeneration, hemangioma, ulcerative colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma Kawasaki (Kawasaki) s disease, juvenile idiopathic arthritis, of Purulent sweat gland inflammation, Sjögren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis and true red blood cell hyperplasia disease.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the BTK-mediated disorder is an immune rejection associated with organ or cell transplantation selected from the group consisting of: an anti-allogeneic antibody-related disorder, before, during or after organ or cell transplantation Allograft rejection related disorders, pre-transplant conditioning for patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, conditions associated with heart transplantation, conditions associated with kidney transplantation, and kidney transplantation Conditions, conditions associated with lung transplantation, conditions associated with liver transplantation, conditions associated with transplantation compatible with ABO, and conditions associated with stem cell transplantation.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the BTK-mediated disorder is graft-versus-host disease (GVHD), wherein the GVHD is selected from A group consisting of GVHD associated with stem cell transplantation, GVHD associated with bone marrow transplantation, thymus GVHD, cutaneous GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and chronic GVHD.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the BTK-mediated condition is a skin disease, wherein the skin disease is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythroderma psoriasis, nail sputum, pustular ring psoriasis , pustular psoriasis, reversal psoriasis, psoriatic arthritis, pussy keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, lipid leak Eczema, liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus fat Inflammation, erythema multiforme, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythema Pediatric, nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse cutaneous mastocytosis, Erythrodermic mastocytosis, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, addiction Acidic dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like pityriasis (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (febrile ulceronecrotic Mucha-Habermann disease) (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft versus host disease, cryoglobulin purpura and hyperglobulinemia purpura .

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber The target BTK occupies, wherein the BTK-mediated condition is a skin disease, wherein the skin disease is caused by a systemic disease in an allergy, a lymphocyte recruitment, a lymphocyte skewing represented by a local or lymph node antigen, and a skin resident Or homing lymphocyte activation, innate immune sensing, keratinocyte anti-microbial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, hobby Skin characterization at neutral spheres and/or Langerhans cells, and where skin diseases cause the development of skin lesions.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period Bruton's tyrosine kinase (BTK) inhibitor; and (b) in the second period Administering a second dose of the BTK inhibitor, wherein the second dose is less than the first dose and is sufficient to provide target BTK occupancy in the tissue chamber, wherein the diagnostic tool is used to assess BTK performance in the BTK-mediated disease and/ Or re-synthesis to determine the optimal therapeutic configuration of the BTK inhibitor.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where diagnostic tools are used to assess BTK performance and/or resynthesis in BTK-mediated diseases to determine optimal treatment configurations for BTK inhibitors, where BTK performance and/or resynthesis assessment occurs Before the treatment of BTK-mediated disorders.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where diagnostic tools are used to assess BTK performance and/or resynthesis in BTK-mediated diseases to determine optimal treatment configurations for BTK inhibitors, where BTK performance and/or resynthesis assessment occurs During the treatment of a condition with BTK media.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where diagnostic tools are used to assess BTK performance and/or resynthesis in BTK-mediated diseases, thereby determining the optimal treatment configuration for BTK inhibitors, where BTK performance and/or resynthesis evaluation is used To identify patients who may benefit from treatment with formula (II).

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where diagnostic tools are used to assess BTK performance and/or resynthesis in BTK-mediated diseases, thereby determining the optimal treatment configuration for BTK inhibitors, where BTK performance and/or resynthesis evaluation is used To identify patients who are unlikely to benefit from treatment with formula (II).

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period Bruton's tyrosine kinase (BTK) inhibitor; and (b) in the second period Administering a second dose of the BTK inhibitor, wherein the second dose is less than the first dose and is sufficient to provide target BTK occupancy in the tissue chamber, wherein the diagnostic tool is used to assess BTK performance in the BTK-mediated disease and/ Or re-synthesis to determine the optimal therapeutic configuration of the BTK inhibitor, wherein the assessment of BTK performance and/or resynthesis is performed using a pharmacodynamic extension of BTK pathway members or BTK pathway activation.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where diagnostic tools are used to assess BTK performance and/or resynthesis in BTK-mediated diseases, thereby determining the optimal treatment configuration for BTK inhibitors, where the diagnostic tool is a kit.

In a preferred embodiment, the invention includes a method of treating a condition of BTK-mediated disease in a human comprising the steps of: (a) administering a first dose sufficient to provide a target BTK occupancy in the tissue chamber during the first period a Bruton's tyrosine kinase (BTK) inhibitor; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less than the first dose and is sufficient to provide a label in the tissue chamber Target BTK occupancy, where diagnostic tools are used to assess BTK performance and/or resynthesis in BTK-mediated diseases, thereby determining the optimal treatment configuration for BTK inhibitors, where the diagnostic tool is a laboratory development assay.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. Wherein the condition is cancer, and wherein the cancer is selected from the group consisting of non-Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma Tumor, mantle cell lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, B cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile bone marrow monocystic leukemia, hypertrophy Cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin cancer, melanoma, eye cancer, visual network Blastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, adenoid cystic carcinoma, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head cancer, neck cancer , kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system cancer, acquired immunodeficiency syndrome-related cancer, child Cervical carcinoma, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary exudative lymphoma, hepatocellular carcinoma, T-cell leukemia, and mastocytosis.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. Wherein the condition is an inflammatory, immunological or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease , skin diseases (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, cystitis, vertebral Arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, suppurative sweat gland inflammation, repair 'S syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis and Polycythemia hyperplasia.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. Wherein the disorder is an immune rejection associated with organ or cell transplantation selected from the group consisting of: a disorder associated with an allogeneic antibody, a disorder associated with allograft rejection before, during or after organ or cell transplantation Pre-transplant conditioning for patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, conditions associated with heart transplantation, conditions associated with kidney transplantation, conditions associated with kidney transplantation, conditions associated with lung transplantation Conditions associated with liver transplantation, conditions associated with transplantation compatible with ABO, and conditions associated with stem cell transplantation.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. The condition is graft versus host disease (GVHD), wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation, GVHD associated with bone marrow transplantation, thymus GVHD, skin GVHD, gastrointestinal GVHD, liver GVHD. , acute GVHD and chronic GVHD.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. The condition is a skin disease, wherein the skin disease is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythrodermic psoriasis, nail sputum, pustular ring psoriasis, pustular psoriasis, reversal Psoriasis, psoriatic arthritis, septic skin keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, lipid leakage eczema, lipid leakage skin Inflammation, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, polymorphism Erythema, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus, nodular Pemphigus, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse cutaneous mastocytosis, erythrodermic hypertrophy Cytomegalox, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphomatoid papulosis, acute Mossy-like acne-like pityriasis (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, Skin characterization of graft versus host disease, cryoglobulin purpura and hyperglobulinemia purpura.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. The disease is a skin disease in which the skin disease is caused by a systemic disease in which allergy, lymphocytic recruitment, lymphocyte degeneration of cells present by local or lymph node antigens, lymphocyte activation of skin resident or skin homing, and innate immune sensing , keratinocyte anti-microbial response, long-term or infiltrating bone marrow dendritic cell activation, plasma cell-like dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans cells, and skin diseases Causes the development of skin lesions.

In a preferred embodiment, the invention includes a method of treating a condition in a human comprising administering a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg, wherein the dose is administered once a day, twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. The human body is a member of a specific group, and the specific group system is selected from the group consisting of: children, adolescents, infants, adolescents, lactating mothers, pregnant women, elderly/weak individuals, patients requiring multiple medications A patient with liver damage, a slow-tolerant or intolerant and/or sensitive individual.

In a preferred embodiment, the invention includes a method of treating a condition BTK-mediated in a human comprising the steps of: (a) administering sufficient to provide a target in the tissue chamber during a second or long-term administration period BTK occupies doses and schedules of BTK inhibitors. In one embodiment, the BTK-mediated disorder is a cancer selected from the group consisting of non-Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, Diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile bone marrow Nucleoblastic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin cancer, melanoma, eye cancer , retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, adenoid cystic carcinoma, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer (cervical cancer), head cancer, Cervical cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system cancer, acquired immunodeficiency syndrome Group-related cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary exudative lymphoma, hepatocellular carcinoma, T-cell leukemia, and mastocytosis. In one embodiment, the BTK-mediated disorder is selected from the group consisting of Group of inflammatory, immune or autoimmune disorders: tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema) And scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, white stopper Disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, suppurative sweat gland inflammation, Sugly's syndrome, psoriatic arthritis, juvenile type Rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis, and true erythrocytosis. In one embodiment, the BTK-mediated disorder is an immune rejection associated with an organ or cell transplant selected from the group consisting of: an anti-allogeneic antibody-related disorder, before, during, or during an organ or cell transplantation. Post-transplantation disorders associated with allograft rejection, pre-transplant conditioning for patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, conditions associated with heart transplantation, conditions associated with kidney transplantation, and kidney transplantation Related conditions, conditions associated with lung transplantation, conditions associated with liver transplantation, conditions associated with transplantation compatible with ABO, and conditions associated with stem cell transplantation. In one embodiment, the BTK-mediated disorder is graft versus host disease (GVHD), wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation, GVHD associated with bone marrow transplantation, and thymus GVHD , skin GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and chronic GVHD. In one embodiment, the BTK-mediated condition is a skin disease, wherein the skin disease system Choose from the following groups: psoriasis vulgaris, psoriasis psoriasis, erythrodermic psoriasis, nail sputum, pustular ring psoriasis, pustular psoriasis, reversal psoriasis, psoriatic arthritis, pus Sexual keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, liposuction eczema, liposuction dermatitis, sweat herpes, rose spots, skin Lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, erythema multiforme, sputum, verrucous lupus erythematosus, white spot , round bald, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus, nodular pemphigoid, erythrodermic meat Tumor, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse cutaneous mastocytosis, erythrodermic mastocytosis, ring granuloma, nodular cartilage skin Inflammation, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like pimples (PLEVA), chronic Mossy-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft-versus-host disease, cryoglobulin Purpura and hyperglobulinemia purpura. In one embodiment, the BTK-mediated disorder is a skin disorder in which the skin disorder results from a systemic disease in which sensitivity, lymphocytic recruitment, lymphocyte degeneration of cells present by local or lymph node antigens, skin persistence or skin homing Lymphocytic activation, innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasma cells Skin characterization at dendritic cells, macrophages, mast cells, neutrophils, and/or Langerhans cells, and wherein skin diseases cause the development of skin lesions. In any of the foregoing embodiments, the treated human body is part of a specific group, wherein the particular group can be selected from the group consisting of: children, adolescents, infants, adolescents, lactating mothers, pregnant women, years Old/weak individuals, patients requiring multiple medications, patients with liver damage, individuals with slow or intolerant and/or sensitive metabolism. In any of the foregoing embodiments, the target BTK occupancy is selected from the group consisting of greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%. In any of the foregoing embodiments, the tissue compartment is selected from the group consisting of peripheral blood B cells, bone marrow B cells, lymph node B cells, autoreactive B cells, plasma cells, regulatory B cells. Follicular dendritic cells, dendritic cells derived from bone marrow, tumor stroma, tumor-associated macrophages, mast cells, alveolar macrophages, dust cells, plasmacytoid dendritic cells, epidermal lymphocyte antigens CLA)-positive T cells, lymphoid cells, Langerhans cells, monocytes, macrophages, histiocytes, Kupffer cells, glial cells, microglia, Schwann cells, Ito cells, hepatic stellate cells, pancreatic stellate Cells, glioma cells, malignant B cells, adipocytes, sarcoma cells, granules, neutrophils, eosinophils, hematopoietic stem cells, serous cells, mesenchymal cells, osteoblasts, osteoclasts, infiltration Lymphocytes, immune cells, and inflammatory exudates. In any of the foregoing embodiments, the tissue compartment is selected from the group consisting of: peripheral blood, Bone marrow, germinal center, lymphoid follicles, lymphoid tissue associated with intestinal tube, tonsil, lymphoma lesions, ectopic lymphoid tissue, ectopic node, lymph node lesions, lymphadenopathy, spleen, solid tumor, tumor microenvironment, tumor stroma , bone, bone lesions, bone metastases, synovial fluid, articular surface, joints, kidneys, liver, lungs, branches/bronchus, mediastinum, pleura, peritoneum, cystadenocarcinoma, heart, pancreas, sinusoids, eyes, Nerve, brain, brain metastasis, brain lesions, central nervous system, skin, stomach, lamina propria, intestinal tract, colon, exocrine gland, salivary gland, lacrimal gland, breast, dermis, subcutaneous tissue, epidermis, perivascular, inflammatory lesions, granuloma , mast cell tumor, papules, test pills, ovaries and bladder.

In a preferred embodiment, the invention includes a method of treating a condition of a BTK-mediated disorder in a human comprising the steps of: (a) administering a BTK inhibitor of a dosage form that provides controlled release of the active pharmaceutical agent over time, The release is sufficient to provide target BTK occupancy in the tissue chamber during the second or long term administration period. In one embodiment, the BTK-mediated disorder is a cancer selected from the group consisting of non-Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, Diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile bone marrow Nucleoblastic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin cancer, melanoma, eye cancer , retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, adenoid cystic carcinoma, bladder Cyst cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer (cervical cancer), head cancer, neck cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone Cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system cancer, acquired immunodeficiency syndrome-related cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary exudation Lymphoma, hepatocellular carcinoma, T-cell leukemia and mastocytosis. In one embodiment, the BTK-mediated disorder is an inflammatory, immunological or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, arteries Atherosclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, ulcerative colitis, Atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, Suppurative sweat glands, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis, and true erythrocytosis. In one embodiment, the BTK-mediated disorder is an immune rejection associated with an organ or cell transplant selected from the group consisting of: an anti-allogeneic antibody-related disorder, before, during, or during an organ or cell transplantation. Post-transplantation disorders associated with allograft rejection, pre-transplant conditioning for patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, conditions associated with heart transplantation, conditions associated with kidney transplantation, and kidney transplantation Related diseases and lung transplantation Conditions, conditions associated with liver transplantation, conditions associated with ABO incompatible transplantation, and conditions associated with stem cell transplantation. In one embodiment, the BTK-mediated disorder is graft versus host disease (GVHD), wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation, GVHD associated with bone marrow transplantation, and thymus GVHD , skin GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and chronic GVHD. In one embodiment, the BTK-mediated condition is a skin disorder, wherein the dermatological condition is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythroderma psoriasis, nail sputum, pustular ring Psoriasis, pustular psoriasis, reversal psoriasis, psoriatic arthritis, pussy keratosis, psoriasis, nodular erythema, glaucoma of the hands and feet, atopic dermatitis, atopic eczema, Liposuction eczema, liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, erythema Lupus panniculitis, erythema multiforme, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus , erythema pemphigus, nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse skin hypertrophy Increased cells , erythrodermic mastocytosis, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymph Tumor-like papulosis, acute lichen-like pimples pimples (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis Fulberry-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft-versus-host disease, cryoglobulin purpura, and hyperglobulinemia purpura. In one embodiment, the BTK-mediated condition is a skin disease, wherein the skin disease is caused by a systemic disease in which allergy, lymphocytic recruitment, lymphocyte degeneration of cells presented by local or lymph node antigens, skin persistence or skin homing Lymphocytic activation, innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans Skin characterization at the cell where the skin disease causes the development of skin lesions. In any of the foregoing embodiments, the treated human body is part of a particular population. In any of the foregoing embodiments, a particular group may be selected from the group consisting of: children, adolescents, infants, adolescents, lactating mothers, pregnant women, elderly/weak individuals, diseases requiring multiple medications A patient suffering from, having liver damage, a slow-tolerant or intolerant and/or sensitive individual. In any of the foregoing embodiments, the target BTK occupancy is selected from the group consisting of greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%. In any of the foregoing embodiments, the tissue compartment is selected from the group consisting of peripheral blood B cells, bone marrow B cells, lymph node B cells, autoreactive B cells, plasma cells, regulatory B cells. Follicular dendritic cells, dendritic cells derived from bone marrow, tumor stroma, tumor-associated macrophages, mast cells, alveolar macrophages, dust cells, plasmacytoid dendritic cells, epidermal lymphocyte antigens CLA)-positive T cells, Lymphotropic cells, Langerhans cells, mononuclear cells, macrophages, histiocytes, Kupffer cells, glial cells, microglia, Schwann cells, Ito cells, hepatic stellate cells, pancreatic stellate cells, glioma cells, Malignant B cells, adipocytes, sarcoma cells, granules, neutrophils, eosinophils, hematopoietic stem cells, serous cells, mesenchymal cells, osteoblasts, osteoclasts, infiltrating lymphocytes, immune cells, and inflammation Sexual exudate. In any of the foregoing embodiments, the tissue compartment is selected from the group consisting of peripheral blood, bone marrow, germinal center, lymphoid follicles, lymphoid tissue associated with the intestine, tonsils, lymphoma lesions, and different Lymphoid tissue, ectopic node, lymph node lesions, lymphadenopathy, spleen, solid tumor, tumor microenvironment, tumor stroma, bone, bone lesion, bone metastasis, synovial fluid, articular surface, joint, kidney, liver, lung, Branch tubules / bronchioles, mediastinum, pleura, peritoneum, cystadenocarcinoma, heart, pancreas, sinusoids, eye, nerves, brain, brain metastasis, brain lesions, central nervous system, skin, stomach, lamina propria, intestinal tract, colon , exocrine glands, salivary glands, lacrimal glands, breast, dermis, subcutaneous tissue, epidermis, perivascular, inflammatory lesions, granuloma, mast cell tumor, papules, testicles, ovaries and bladder.

In a preferred embodiment, the invention includes a pharmaceutical composition comprising a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable excipient, wherein the dosage is selected from the group consisting of 5 mg, 10 Mg, 15 mg, 20 mg and 25 mg, and wherein the composition is suitable for topical delivery. In a preferred embodiment, the present invention provides the use of a pharmaceutical composition according to any of the preceding embodiments for the manufacture of a medicament for the treatment of a skin condition. In a preferred embodiment, the dermatological condition is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythrodermic psoriasis, nail sputum, pustular ring psoriasis, pustular psoriasis, Anti-transformation psoriasis, psoriatic arthritis, septic skin keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, lipid leakage eczema, lipid leakage Dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, polymorphism Erythema, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus, nodules Pemphigus, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse cutaneous mastocytosis, erythroderma Mast cell enlargement , ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, acute moss-like Pock-like pityriasis (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, graft resistance Skin characterization of host disease, cryoglobulin purpura and hyperglobulinemia purpura. In a preferred embodiment, the skin disease is caused by a systemic disease in which sensitivity, lymphocytic recruitment, lymphocyte degeneration of cells present by local or lymph node antigens, lymphocyte activation of skin resident or skin homing, innate immunity Skin characterization of sensing, keratinocyte antimicrobial response, growth or infiltration of bone marrow dendritic cells, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans cells, and wherein Skin diseases cause the development of skin lesions.

In a preferred embodiment, the invention includes a method of treating a skin condition comprising the step of administering a therapeutically effective amount of a BTK inhibitor. In one embodiment, the dermatological condition is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythrodermic psoriasis, nail sputum, pustular ring psoriasis, pustular psoriasis, reversal Psoriasis, psoriatic arthritis, septic skin keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, liposuction eczema, lipid leakage skin Inflammation, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, erythema multiforme , sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus, nodular Pemphigus, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse cutaneous mastocytosis, erythrodermic mast cells Hyperplasia, Ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like acne Pityriasis (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophil dermatitis, graft versus host Diseased skin characterization, cryoglobulin purpura and hyperglobulinemia purpura. In one embodiment, the skin disease is caused by a systemic disease in which allergy, lymphocytic recruitment, lymphocyte degeneration of cells present by local or lymph node antigens, lymphocyte activation of skin resident or skin homing, and innate immune sensing , keratinocyte anti-microbial response, long-term or infiltrating bone marrow dendritic cell activation, plasma cell-like dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans cells, and skin diseases Causes the development of skin lesions. In a preferred embodiment, the dermatological condition is selected from the group consisting of psoriasis, scleroderma, atopic dermatitis, and cutaneous lupus erythematosus. In any of the foregoing embodiments, the BTK inhibitor is selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof. In any of the foregoing embodiments, the therapeutically effective dose of the BTK inhibitor is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 45 mg, 60 Mg, 75 mg, 90 mg, and 100 mg, wherein the therapeutically effective dose is administered at intervals selected from the group consisting of: once daily, twice daily, three times daily, and four times daily, and wherein the therapeutically effective dose is It is administered by a route selected from the group consisting of oral administration, topical administration, and combinations thereof.

In one embodiment, the invention includes a composition and method for treating leukemia, the disease exhibiting a higher rate of BTK resynthesis in leukemia bone marrow B cells than in BTK blood B cells in leukemia blood B cells, the method A step comprising administering a dose of a compound to reduce the rate of BTK resynthesis, wherein the compound is a BTK covalent inhibitor. In one embodiment, the invention includes a composition and method for treating leukemia, the disease exhibiting a higher rate of BTK resynthesis in leukemia bone marrow B cells than in BTK blood B cells in leukemia blood B cells, the method A step comprising administering a dose of a compound to inhibit BTK and reducing the rate of recombination of BTK, wherein the compound is a compound of formula (I) to formula (XXV), the dose being administered once daily, twice daily or three times daily, and the leukemia is Chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), Richter's transformation (RT) , mantle cell lymphoma (MCL), Burkitt's lymphoma (BL) or Waldenstrom's macroglobulinemia (WM).

In one embodiment, the invention includes a method of treating leukemia, the disease exhibiting a higher rate of BTK resynthesis in leukemic bone marrow B cells than in a leukemia lymph node B cell, the method comprising administering Compound dose is a step of inhibiting BTK and reducing the rate of BTK resynthesis, wherein the compound is a compound of formula (I) to formula (XXV), and the dose is administered once a day, twice a day or three times a day, and the leukemia is CLL, SLL , DLBCL, RT, MCL, BL or WM.

In one embodiment, the invention includes a method of treating acute leukemia, the disease exhibiting a higher rate of BTK resynthesis in blood B cells of acute leukemia than a rate of BTK resynthesis in blood B cells of chronic leukemia, the method A step comprising administering a dose of a compound to inhibit BTK and reducing the rate of recombination of BTK, wherein the compound is a compound of formula (I) to formula (XXV), the dose being administered once daily, twice daily or three times daily, and the leukemia is B cell acute lymphoblastic leukemia (B-ALL), BL, pro-lymphocytic leukemia or Ricker's transformation.

In one embodiment, the invention includes a method of treating a B cell malignant disease, the disease exhibiting a higher rate of BTK resynthesis in a peripheral lymph node with lymphadenopathy than a BTK resynthesis rate in circulating tumor cells or bone marrow High, the method comprises the steps of administering a dose of a compound to inhibit BTK and reducing the rate of recombination of BTK, wherein the compound is a compound of formula (I) to formula (XXV), the dose being administered once daily, twice daily or three times a day. And B cell malignant diseases are DLBCL, RT, MCL, BL, WM, follicular lymphoma (FL), large B-cell lymphoma rich in T cells/tissue cells, EBV-positive DLBCL in the elderly, primary Skin DLBCL, primary DLBCL of the central nervous system, primary mediastinal large B-cell lymphoma, Castleman's disease transition, unclassified B-cell lymphoid with DLBCL and Hodgkin's disease characteristics Tumor or Hodgkin's lymphoma.

In one embodiment, the invention includes a method of treating a B cell disorder, the disorder showing a higher rate of BTK resynthesis in a peripheral lymph node with lymphadenopathy than in circulating B cells or normal developing bone marrow The BTK resynthesis rate is higher, the method comprises the steps of administering a compound dose to inhibit BTK and reducing the rate of BTK resynthesis, wherein the compound is a compound of formula (I) to formula (XXV), and the dosage is administered once a day, Twice a day or three times a day, and the disease treated is a post-transplant lymphoproliferative disorder, lymphoma granuloma or chronic fatigue syndrome.

In one embodiment, the invention includes a method of treating an autoimmune disease, the disease exhibiting a rate of BTK resynthesis in a tissue disease site that is greater than BTK in circulating peripheral blood B cells or normally developing bone marrow B cells. The synthesis rate is higher, the method comprises the steps of administering a compound dose to inhibit BTK and reducing the rate of BTK resynthesis, wherein the compound is a compound of formula (I) to formula (XXV), and the dosage is administered once a day, twice a day. Or three times a day, and the autoimmune disease is rheumatoid arthritis, juvenile RA, osteoarthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis vulgaris, pemphigus vulgaris, pemphigus pemphigus, Singer's syndrome (SS), systemic lupus erythematosus (SLE), discoid lupus erythematosus (disc LE), LE swelling, lupus nephritis (LN), antiphospholipid lesions, pancreatic duodenal resection (whipple), Dermatomyositis, polymyositis, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, thrombotic small reduced purpura, autoimmune (cold) lectin disease, autoimmune hemolytic anemia, Condenoglobulinemia, autoimmune vasculitis, ANCA-associated vasculitis, scleroderma, systemic sclerosis, multiple sclerosis (MS), chronic local encephalitis, Guillian-Barre Syndrome, chronic fatigue syndrome, mononucleosis, optic neuromyelitis, autoimmune uveitis, Grave's disease, Thyroid-associated ophthalmopathy, granuloma with microscopic polyangiitis, Wegeners granulomatosis, idiopathic pulmonary fibrosis, sarcoma-like disease, idiopathic membranous nephropathy, IgA nephropathy, glomerular sclerosis Symptoms, pancreatitis, type 1 diabetes, and type 2 diabetes.

In one embodiment, the invention includes a method of treating an autoimmune disease, the disease exhibiting a rate of BTK resynthesis, which can be quantified in a co-valent assay using a suitable assay in cells from diseased tissue or peripheral blood. The unoccupied BTK target site present at a particular time point after inactivation of the BTK kinase agent was measured. The unoccupied BTK target site present in the relevant cells can be assayed by enzyme-linked immunosorbent assay (ELISA), flow cytometry, ligand binding assay on beads, immunohistochemistry or related assays. Other in-vitro diagnostic techniques for measuring methods. A method of treating a particular disease based on the rate of BTK regeneration in a diseased tissue comprises measuring the rate of BTK resynthesis in a patient or group of patients with a particular disease and administering a dose of the compound to inhibit BTK and reduce the rate of BTK resynthesis A step wherein the compound is a compound of formula (I) to formula (XXV) and the dosage is administered once daily, twice daily or three times daily depending on the measured rate of BTK resynthesis.

In one embodiment, the invention includes a method of treating an autoimmune disease, a method of treating an inflammatory, immune, and autoimmune disease, and a method of inhibiting an immune response of an organ or a cell transplant, wherein the cancer, disease, or inhibition The immune response reveals a rate of BTK resynthesis that can be used at the disease site to detect specific imaging agents present in the unoccupied BTK target site with CT scans, positron emission tomography (PET) imaging, and magnetic resonance. Measured by contrast (MRI) or near-infrared fluorescence imaging or other in vivo imaging modalities that are tailored to treat specific diseases based on the rate of BTK regeneration in diseased tissue.

In one embodiment, the method comprises the steps of measuring a rate of BTK resynthesis in a patient or a group of patients having a particular disease and administering a dose of the compound to inhibit BTK and reduce the rate of BTK resynthesis, wherein the compound is (I) to a compound of formula (XXV), and the dosage is administered once daily, twice daily or three times daily depending on the measured rate of BTK resynthesis.

In one embodiment, the invention includes a method of treating a B cell malignant disease, the disease exhibiting a rate of BTK resynthesis, which can be in a cell from an affected lymph node, bone marrow, peripheral blood, or other diseased site (such as metastasis) The measurement is performed by quantifying the presence of an unoccupied BTK target site at a specific time point after administration of a covalently bound and inactivated BTK agent using a suitable assay. The unoccupied BTK target site present in the relevant cells can be assayed using ELISA, flow cytometry, ligand binding assay on beads, immunohistochemistry or other in vitro diagnostic techniques with associated detection methods. measuring. A method of treating a particular B cell malignant disease based on the rate of BTK regeneration in tumor cells comprises measuring the rate of BTK resynthesis in an individual or group of individuals with a malignant disease and administering a compound dose to inhibit BTK and reduce BTK. The step of synthesizing the rate wherein the compound is a compound of formula (I) to formula (XXV), and the dosage is administered once a day, twice a day or three times a day depending on the measured rate of BTK resynthesis.

In one embodiment, the invention includes a method of treating a B cell malignancy that exhibits a rate of BTK resynthesis that can be used in a tumor-bearing tissue and bone marrow to detect the presence of an unoccupied BTK target site. The imaging agent is measured in combination with CT scan, PET imaging, MRI or NMR imaging, or other in vivo imaging modalities for assessing disease activity, which is a customized treatment of B cells based on the rate of BTK regeneration in the tumor-bearing tissue. Malignant disease. The method comprises the steps of measuring a rate of BTK resynthesis in an individual or group of individuals having a particular disease and administering a dose of the compound to inhibit BTK and reduce the rate of BTK resynthesis, wherein the compound is of formula (I) to formula (XXV) The compound, and the dosage, is administered once daily, twice daily or three times daily depending on the measured rate of BTK resynthesis.

In one embodiment, the invention includes a method of treating a B cell malignancy that exhibits a different rate of BTK resynthesis with different lesions, which can be used to detect the presence of an unoccupied BTK target site. The imaging agent is measured in combination with CT scan, PET imaging, MRI or NMR imaging, or other in vivo imaging modalities for assessing disease activity, which is a customized treatment for BTK regeneration rate in a subpopulation of tumor lesions in the human body. Basic B cell malignancy. The method comprises the steps of measuring the rate of BTK resynthesis in a number of lesions (such as index lesions, lesions with rapid metabolism, and newly emerging lesions in the body) and administering a dose of the compound to inhibit BTK and reduce the rate of BTK resynthesis, wherein the compound is a compound of formula (I) to formula (XXV), and the dosage depends on the fastest measured BTK recombination in individual patients or groups of patients or subgroups of patients with malignant diseases The rate is set to be administered once a day, twice a day or three times a day.

In one embodiment, the invention includes a method of treating a BTK-positive disease, wherein the BTK resynthesis is monitored by in vitro or in vivo measurements on the diseased tissue site after administration of the BTK covalent inhibitor, wherein the compound a compound of formula (I) to formula (XXV), and the diseased tissue site is a chamber containing a different rate of BTK resynthesis than other chambers in the body, such as a peripheral blood chamber or a bone marrow chamber, and is used in a chamber containing the diseased tissue. The rate of resynthesis defines the dose value, dosage schedule or dosage form of the inhibitor.

In one embodiment, the invention includes a method of treating a BTK-positive disease, wherein the BTK resynthesis is monitored by in vitro or in vivo measurements on the diseased tissue site after administration of the BTK covalent inhibitor, wherein the compound a compound of formula (I) to formula (XXV), and the rapidly growing tumor lesion is a chamber containing a different rate of BTK resynthesis than other chambers in the body, such as a peripheral blood chamber or a chamber associated with a more painless tumor lesion, and The dose rate, dose schedule or dosage form of the inhibitor is defined using the rate of resynthesis in a chamber containing rapidly growing tumor lesions.

In one embodiment, the invention includes a method of treating CLL, wherein the BTK resynthesis is monitored by in vitro or in vivo measurements on a diseased tissue site following administration of a BTK covalent inhibitor, wherein the compound is (I) to a compound of formula (XXV), and the bone marrow is a chamber containing a different rate of BTK resynthesis than other chambers in the body, such as a peripheral blood chamber or CLL cells hosted in body lymphoid tissues or other tissues including bone marrow. And using a resynthesis rate-defining inhibitor in a chamber containing bone marrow Dosage value, dose schedule or dosage form.

In one embodiment, the invention includes a method of treating RA, wherein the BTK resynthesis is monitored by in vitro or in vivo measurements on a diseased tissue site following administration of a BTK covalent inhibitor, wherein the compound is (I) to a compound of formula (XXV), and the synovial fluid is a chamber containing a different rate of BTK resynthesis than other chambers in the body, such as a peripheral blood chamber or a chamber containing lymphoid tissue, and is used in a chamber containing synovial fluid The rate of resynthesis defines the dose value, dosage schedule or dosage form of the inhibitor.

In one embodiment, the invention includes a method of treating an autoimmune disease, wherein the BTK resynthesis is monitored by in vitro or in vivo measurements on the diseased tissue site after administration of the BTK covalent inhibitor, wherein The compound is a compound of formula (I) to formula (XXV), and the tissue affected by the autoimmune disease activity comprises a chamber having a different rate of BTK resynthesis than other chambers in the body, such as a peripheral blood chamber or a chamber containing lymphoid tissue. And the dosage rate, dosage schedule or dosage form of the inhibitor is defined using the rate of resynthesis in the chamber containing the diseased tissue.

In one embodiment, the invention includes a method of treating a patient receiving an HLA-unpaired or incompletely matched graft, wherein the BTK resynthesis is in a graft or an allogeneic species after administration of a BTK covalent inhibitor The tissue site affected by allogeneic immunity is monitored by means of in vitro or in vivo measurements, wherein the compound is a compound of formula (I) to formula (XXV), and the tissue affected by the anti-allogene immunological activity comprises having other chambers in vivo Different BTK resynthesis rate chambers, such as peripheral blood chambers or chambers containing unstimulated immune cells, and recombination in a chamber containing diseased tissue The rate defines the dose value of the inhibitor, the dosage schedule or the dosage form.

In one embodiment, the invention includes a method of treating a BTK positive disease with a controlled release formulation of a BTK covalent inhibitor, wherein the compound is a compound of formula (I) to formula (XXV), and the controlled release formulation Sufficient strength absorbed from the drug delivery site is provided into the primary compartment (peripheral blood) and into the diseased tissue compartment, and thereby inhibiting BTK and reducing the rate of BTK synthesis throughout the dosing interval. Controlled release may include extended release and delayed release, or extended, delayed, and immediate release formulations in a single unit dose or a combination of separate unit doses. Controlled release formulations include a single infusion in which a compound is targeted to a single region of the gastrointestinal (GI) tract, a single infusion or targeted to a particular region of the mammalian GI tract or a targeted segment (its Formulations that are delivered by multiple infusions including, but not limited to, the stomach, duodenum, jejunum, ileum, cecum, colon, rectum, or anus. Controlled release can be based on polymers or excipients that dissolve or form pores at specific pH, swell to inhibit GI transport or post-release, react at different pHs to reduce formulation density and cause buoyancy Retaining units, and/or having specific chemical or physical properties that allow them to react to specific conditions in different regions of the GI tract, including but not limited to bile salts, ionic strength, enzymes, pH, volume, microbiota or time effect.

In one embodiment, the invention includes a method of treating a BTK positive disease, the dosage configuration comprising a higher loading dose sufficient to reduce the rate of BTK resynthesis in the tissue chamber of interest after a period of time, in an extended or long term A sufficient maintenance dose to inhibit BTK during the drug phase. Loading dose to get BTK inhibition and maintenance dose to reach steady state quickly A sustained BTK inhibition is obtained following a decrease in the rate of BTK resynthesis in the tissue chamber of interest.

The foregoing summary of the invention, as well as the following detailed description

Figure 1A illustrates a two-compartment PK mode with delayed oral absorption, which was used to fit a concentration of time-to-time data from a healthy volunteer to 15 mg of Formula (II) over 7 days. The mode is a two-compartment PK mode with oral absorption at a delay of d (1, 3). Room q1 represents the primary room (ie blood or circulatory system), room q2 represents the drug delivery point (ie the general intestine, stomach and / or duodenum), and room q4 represents the surrounding room, rate k (3, 2), k (4,1) and k(1,4) represent the interventricular rate, the rate k(0,1) represents the output rate (ie BTK degradation), and s1 represents the sampling point (ie blood or circulatory system). Figures 1B, 1C show the observed (solid sign) versus mode (solid line) mean concentration-time profile for the formula (II) after the 15 mg dose. The 7th day contour was derived from the pattern fitting on Day 1 (Fig. 1B), and the 7th day data was added (Fig. 1C). Pattern fitting does not use unweighted data.

Figure 2 illustrates the biological phase PD pattern of the chamber used to fit the BTK occupancy data of formula (II), where q7 compartment represents unmodified BTK (i.e., BTK not covalently bound to formula (II)), q6 compartment represents Covalently bound to the BTK of formula (II), and each chamber has a transfer rate (input rate - output rate). Assume that the output rate k(0,7) is equal to k(0,6). The rate constant k(6,7) is the saturable rate constant, which represents the irreversible BTK deactivation of formula (II). The PK mode and the PD mode are linked by a rate constant k (6, 7) which is a saturable constant and contains a drug concentration C term (drug concentration in the chamber q1 (Fig. 1)). The occupancy of the receptor is determined by the ratio: q6/(q6+q7). Symbol s2 represents a sampling point (i.e., blood or central chamber) that captures both functional (unbound) BTK and inactivated BTK as a target occupancy percentage.

Figure 3 exemplifies the BTK occupancy of the PK/PD pattern in healthy volunteers after 7 days of repeated doses of 15 mg. The inactivated BTK line present in the peripheral blood B lymphocytes was measured in the ELISA assay using a BTK active site specific probe and expressed as a percentage of pre-study content. The mode shift rate changes over time; the pattern fit does not use unweighted data.

4A and 4B illustrate the effect of BTK resynthesis rate over time during the treatment of formula (II) based on the initial pattern fit of day 1 and day 7 steady state data. The inactivated BTK line present in the peripheral blood B lymphocytes was measured in an ELISA assay using a BTK active site specific probe. The percentage of BTK target occupancy during the treatment and post-dosing intervals was measured and the rate of BTK re-synthesis after initial administration (t _1/2 = 20 hours, Figure 4A) and subsequent BTK re-synthesis rate (t _{1 ) were} measured. _/2 = 119 hours, pattern fitting of Figure 4B).

Figure 5 illustrates the PK/PD pattern fit of BTK phosphorylation inhibition in healthy human volunteers administered with 15 mg of Formula (II) QD. The percentage of BTK functional activation was measured using phosphoric acid-flow cytometry after in vitro BCR stimulation of peripheral blood B cells. Fit estimates (solid lines) and data from healthy volunteer studies.

Figure 6A and Figure 6B are based on the PK/PD model derived from the Healthy Volunteer Institute on the first day (Figure 6A) and Day 7 (Figure 6B) at a single oral delivery of 25 mg (based on the PK/PD model derived from the Healthy Volunteer Institute ( II) Plasma concentration time profile. The actual data from 40 healthy human volunteers treated with 25 mg of formula (II) from study day 1 and study day 7 were included.

Figures 7A, 7B, and 7C illustrate BTK target occupancy and two PK/PD pattern estimates in healthy human volunteers. Figure 7A illustrates BTK target occupancy in peripheral blood B lymphocytes from healthy human volunteers (n=40) after two 25 mg (II) oral doses separated by one week. The inactivated BTK line present in the peripheral blood B lymphocytes was measured in an ELISA assay using a BTK active site specific probe. The percentage of BTK target occupancy during the treatment and post-dosing intervals is shown and a linear regression describing the rate at which the BTK target occupies a T=4 hour post-dose peak decline. The linear correlation of the BTK target for terminal phase decay was statistically significant (p < 0.0001), although the linear curve fit only approximated the elimination phase kinetics occupied by the BTK target, as determined by the PK/PD mode. The PK/PD model estimate of the 25 mg (II) dose showed a complete fit of the BTK Occupancy Study on Day 1 (Figure 7B) and Study Day 7 (Figure 7C) after the second dose, but the BTK resynthesis rate Faster after the initial dose.

Figure 8 illustrates the percentage of BTK target occupancy simulated using the PK/PD model to estimate the PD effect of 15 mg of Formula (II) BID and 30 mg of Formula (II) QD administration.

Figure 9 illustrates the use of PK/PD mode simulation of BTK to occupy 100 The ratio was estimated to estimate the PD effect of 15, 30 and 45 mg of formula (II) QD administration.

Figure 10 illustrates the percentage of BTK occupancy simulated using the PK/PD pattern to estimate the PD effect of 15, 30 and 45 mg of Formula (II) BID administration.

Figure 11 illustrates the percentage inhibition of BTK phosphorylation by PK/PD simulation using the PK/PD model to estimate the effect of 15 mg BID on the pBTK inhibition of dose configuration of formula (II) of 30 mg QD.

Figure 12 illustrates a pattern fit of the concentration versus time profile of formula (II) in an individual orally administered at a dose of 50 mg of formula (II). To simulate a dose above 25 mg, the rate of fixation of mode k (4, 1) was reduced. Data from 50 mg of healthy volunteers treated with formula (II).

Figure 13 illustrates the simulated BTK occupancy from the BTK resynthesis step to the lower rate final PK/PD mode after day 2 of administration with 100 mg of the formula (II) QD. Percent BTK occupancy data for patients with CLL treated with this dose configuration. The inactivated BTK line present in CLL tumor cells was measured using an BTK active site specific probe in an ELISA assay.

Figure 14 illustrates the simulated BTK occupancy from the BTK resynthesis step to the lower rate final PK/PD mode after day 2 of administration with 100 mg of the formula (II) BID. The average BTK occupancy percentage data for individuals with CLL who were treated with this dose configuration. The inactivated BTK line present in CLL tumor cells was measured using an BTK active site specific probe in an ELISA assay.

Figure 15 illustrates the simulated BTK occupancy from the final PK/PD mode with a BTK resynthesis step to a lower rate after the second day of administration at a dose of 250 mg of the formula (II) QD. Percent BTK occupancy data for patients with CLL treated with this dose configuration. The inactivated BTK line present in CLL tumor cells was measured using an BTK active site specific probe in an ELISA assay.

Figure 16 illustrates the simulated BTK occupancy from the BTK resynthesis step to the lower rate final PK/PD mode after the second day of administration at a dose of 400 mg of the formula (II) QD. The average BTK occupancy percentage data for individuals with CLL who were treated with this dose configuration. The inactivated BTK line present in CLL tumor cells was measured using an BTK active site specific probe in an ELISA assay.

Figure 17 illustrates the PK/PD simulated BTK occupancy in a 30 mg QD versus 15 mg BID formula (II) administration configuration.

Figure 18 illustrates PK/PD simulated BTK occupancy at a loading dose of 60 mg BID loading dose followed by a 30 mg QD maintenance dose in a loading dose, maintenance dose configuration of formula (II).

Figure 19 illustrates the PK/PD simulated BTK occupancy in a loading dose, maintenance dose configuration of formula (II) at a 60 mg BID loading dose over 7 days followed by a 15 mg QD maintenance dose.

Figure 20 illustrates PK/PD simulated BTK occupancy at a loading dose of 60 mg BID loading dose followed by a 7.5 mg QD maintenance dose in a loading dose, maintenance dose configuration of formula (II).

Figure 21 illustrates BTK target occupancy data and pattern fit in peripheral blood B lymphocytes from healthy human volunteers (n=40) during 7 days of oral administration of 15 mg of Formula (II) QD. The inactivated BTK line present in the peripheral blood B lymphocytes was measured in an ELISA assay using a BTK active site specific probe. The percentage of BTK target occupancy and the modeled estimate during the post-treatment and post-dosing intervals were based on a BTK resynthesis rate of 0.91 k _4,1 and 0.1 and 48 hours after the first 48 hours. Patterned estimates do not use unweighted data points.

Figure 22 illustrates the effect of oral administration of 15 mg of the formula (II) QD for 7 consecutive days on the intracellular BTK total protein content in peripheral blood B lymphocytes. The percentage of BTK protein content prior to study in cryopreserved B cells was determined by mean fluorescence intensity analyzed by flow cytometry. A reduced BTK content was observed after 48 hours.

Figure 23A and Figure 23B illustrate healthy human volunteers treated with a single oral dose of formula (II) at 50, 75 and 100 mg doses (QD) or two 25 and 50 mg doses (BID) separated by 12 hours. The rate of BTK resynthesis. The percentage of inactivated BTK present in peripheral blood B lymphocytes was measured using an BTK active site specific probe in an ELISA assay. The percentage of BTK target occupancy during the treatment and post-dosing intervals is shown in Figure 23A. The regression linear regression of the BTK target occupancy from the sample taken 3 hours after the last dose until the end of the monitoring interval was calculated using GraphPad Prism (Fig. 23B).

Figure 24A, Figure 24B, Figure 24C, Figure 24D, Figure 24E, and Figure 24F illustrate the administration of the oral dose of formula (II): 2.5 mg BID, 5 mg BID, 25 mg BID, 50 mg BID, 50 mg The effect of 12-hour QD, 75 mg QD, and 100 mg QD on the signaling function of BCR media in healthy volunteers. Percentage of inhibition of BTK target occupancy by individual Cmax and AUC values (Figures 24A and 24B) and percent inhibition of CD86 and CD69 (Figures 24E and 24F) by BCR stimulation (Figures 24C and 24D).

Figure 25 illustrates B cell function recovery in healthy human volunteers after treatment with 15 mg of formula (II) over the last 7 daily oral doses of 7 days. Unmodified BTK lines were measured in ELISA assays using BTK active site specific probes. Phosphorylated BTK and S6 protein lines were measured by phospho-flow cytometry 15 minutes after BCR stimulation; surface up-regulation of CD69 and CD86 and down-regulation of CXCR4 in B from frozen PBMC preparations sampled at specified times Flow cytometry was measured 24 hours after BCR stimulation in lymphocytes.

26A, 26B, 26C, 26D, and 26E illustrate the concentration versus time profile of formula (II) when administered to a rat at 30 mg/kg/day by oral administration after 14 days of administration. In a rat diet, a diet of 100 and 500 ppm concentrations was compared. The percentage of BTK target occupancy in rat spleens was assessed on day 14. Mean pharmacokinetic parameters from the cohort of 6 male rats were shown in the inset; BTK target occupancy was assessed in the ELISA assay using BTK active site specific probes (n=3).

Figure 27A and Figure 27B illustrate B cell function recovery following treatment of mice with three BTK inhibitors. The expression of CD86 and CD69 after spleen cells were stimulated with anti-IgM was orally administered to mice with BTK inhibitors. The time after the indicated dose is assessed. The percentage of BTK target occupancy is noted in Figure 27C, demonstrating the rate of resynthesis of unmodified BTK in this mouse mode.

28A and 28B exemplify the post-dose evaluation of the dose after functional administration of BCR following stimulation of spleen cells with anti-IgM after oral administration of BTK inhibitors to mice. The base value and stimulation value of the phosphorylated S6 protein were monitored over time.

Figures 29A and 29B illustrate recovery of signaling function via BCR media after treatment with two BTK inhibitors. The performance of CD86 and CD69 after stimulation of splenocytes with anti-IgM was assessed after the indicated dose of BTK inhibitor after oral administration to mice.

Figure 30 illustrates BTK targets in peripheral blood CD21+ B cell samples from dogs with spontaneous canine lymphoma and fine needle extracts from lymphoma lesions after oral administration of formula (II) at the indicated time occupy.

31A, 31B, 31C, and 31D illustrate BTK targets in CD5 ⁺ /CD19 ⁺ tumor cells of patients with relapsed/refractory CLL who are orally administered at the indicated doses of formula (II). occupy. Peripheral blood samples were obtained over time and BTK target occupancy was assessed using BTK active site specific probes in an ELISA assay.

Figure 32 illustrates BCR-mediated levels of BCR-mediated via BTK in patients with chronic lymphocytic leukemia treated orally with formula (II) at the indicated times. A peripheral blood sample was obtained and BTK activity in CD19 ⁺ /CD5 ⁺ tumor cells was assessed by phospho-flow cytometry of p-BTK 15 minutes after BCR stimulation. The BCR-mediated communication system through BTK was significantly inhibited after treatment with formula (II).

Figure 33 illustrates the BTK content of each of the cells with chronic lymphocytic leukemia treated orally with 100 mg of the formula (II) BID at the indicated times. Peripheral blood samples were obtained and BTK activity in CD19+/CD5+ tumor cells was assessed by flow cytometry. After 4 weeks of treatment, the BTK protein exhibited an average reduction of 26% of the pre-dose value, demonstrating that treatment with Formula (II) not only inhibits the functional activity of BTK in tumor cells but also inhibits its rate of resynthesis in treatment-related compartments.

Figure 34 illustrates the rate of BTK resynthesis in patients with chronic lymphocytic leukemia treated with 100 mg of formula (II) QD and 100 mg of formula (II) BID. Unmodified BTK lines present 4 hours after dosing and at the end of the dosing interval were measured in the ELISA assay using BTK active site specific probes and expressed as a percentage of the pre-study values for each patient. The slope of the two lines represents the relative rate of BTK regeneration upon administration on day 8 (after reaching a steady state).

Figures 35A and 35B illustrate the effect of vehicle (left panel) and formula (II) (right panel) on the flux at two time points in the ID8 and base-source orthotopic ovarian cancer model.

Figure 36 illustrates tumor microenvironmental responses treated with a BTK inhibitor of formula (II) in tumor-bearing mice, significantly reducing immunosuppressive tumor-associated lymphocytes and bone marrow cells compared to control (vehicle) and Increase cytolytic lymphocytes.

Figure 37 illustrates that treatment with a BTK inhibitor of formula (II) detracts from ID8 ovarian cancer growth in an ID8 homologous murine model compared to a control (vehicle).

Figure 38A and Figure 38B illustrate that tumor treatment with a BTK inhibitor of formula (II) induces a tumor response that correlates with a significant reduction in total B cells and regulatory B cells (Breg) in the ID8 tumor microenvironment.

Figure 39A and Figure 39B illustrate that treatment with a BTK inhibitor of formula (II) induces tumors associated with increased tumor infiltrating CD8 ⁺ T cells and reduced immunosuppressive tumor infiltrating Tregs in an ID8 homologous murine model. reaction.

Figures 40A, 40B, 40C, 40D, 40E, 40F, and 40G illustrate transplantation of MDA-MB231 tumor allografts in the tibia with a vehicle control, zoledronate ( Bone mineral density after treatment of active rats) or different doses of formula (II) for nude rats up to 41 days (n=6 per group). The time course of formula (II) administered via oral administration was initially administered in QD for 3 days, followed by 30 days at the following doses of BID: 3/3, 30/30 and 180/90 mg/kg/day. The untreated rat group without naw graft (n=3) represents the bone density of the normal rat tibia image obtained at the same time. Statistical significance was determined by two-way ANOVA-Dunnett versus Group 1: ns = no significant, * = P < 0.05, ** = P < 0.01, *** = P < 0.001.

41A, 41B, 41C, 41D, 41E, and 41F illustrate the treatment of formula (II) against keyhole limpet hemocyanin (KLH) T cells in male rats. antibody The effect of the development of the reaction. Each group of 16 male rats was inoculated with a subcutaneously injected antigen on the 50th day of treatment with formula (II). Peripheral blood was sampled at 1, 2, and 3 weeks after KLH inoculation and KLH-specific IgM and IgG levels were measured by ELISA. Raw serum concentration data from the treatment group was compared to the vehicle-treated control using a non-parametric Kruskal-Wallis ANOVA with post-hoc Dunn's test. The indicated significance level: p < 0.05; ** p < 0.01.

Figure 42A, Figure 42B, Figure 42C, Figure 42D, Figure 42E, and Figure 42F illustrate the development of anti-Keyhole limpet hemocyanin (KLH) T cell-dependent antibody response in female rats. effect. Each group of 16 female rats was inoculated with a subcutaneously injected antigen on the 50th day of treatment with formula (II). Peripheral blood was sampled at 1, 2, and 3 weeks after KLH inoculation and KLH-specific IgM and IgG levels were measured by ELISA. Raw serum concentration data from the treatment group was compared to the non-parametric Kruskal-Wallis ANOVA with the hindered Duchen test compared to the vehicle treated control. Indicated significance levels: * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001.

Figure 43 illustrates the relative protein expression of BTK in various cell types and tissues. The numbers are taken from the BTK GeneCard (available from: genecard.org).

Figure 44 illustrates the BTK target occupancy data. Mouse spleen cells (which are part of a half-treatment protocol for mouse CIA studies) were isolated from the spleens of mice 3 hours after the last dose on the 14th day of treatment and spleen cells were cryopreserved. After thawing, the BTK target occupies the spleen of the treatment group Cell sediment measurement. The BTK target occupancy is calculated based on the luminescent signal relative to the vehicle control. Error bars represent the standard deviation of the three groups of splenocytes analyzed.

Figure 45 illustrates a change in the functional metric of BCR messaging through a CD86 marker. Mouse spleen cells (which are part of a half-treatment protocol for mouse CIA studies) were isolated from the spleens of mice 3 hours after the last dose on the 14th day of treatment and spleen cells were cryopreserved. After thawing, the inhibition of the anti-IgM-induced PD markers CD86 and CD69 was measured by mouse spleen B cells. Error bars represent the standard deviation of the three groups of splenocytes analyzed.

Figure 46 illustrates a change in the functional metric of BCR signaling by the CD69 marker. Mouse spleen cells (which are part of a half-treatment protocol for mouse CIA studies) were isolated from the spleens of mice 3 hours after the last dose on the 14th day of treatment and spleen cells were cryopreserved. After thawing, the inhibition of the anti-IgM-induced PD markers CD86 and CD69 was measured by mouse spleen B cells. Error bars represent the standard deviation of the three groups of splenocytes analyzed.

Detailed description of the invention

While the preferred embodiment of the present invention has been shown and described, the embodiments of the present invention are not intended to limit the scope of the invention. The invention may be practiced in various alternative ways of carrying out the embodiments described herein.

definition

All technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art of the invention, unless otherwise defined. All patents and publications mentioned herein are incorporated herein by reference in their entirety.

The term BTK-mediated disease or BTK-mediated condition means that the BTK signaling pathway regulated in the cell modulates the disease or condition such that the disease or condition can be treated or prevented; or that the disease can be alleviated or ameliorated or Illness.

The term "co-administration" and "administered in combination with" as used herein includes administering two or more agents to an individual such that the two agents and/or Or their metabolites are present in the individual at the same time. Co-administration includes administration of separate compositions at the same time, administration at separate compositions at different times, or compositions in which two agents are present.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or a combination of compounds as described herein sufficient to achieve the intended application, including but not limited to disease treatment. The therapeutically effective amount will vary depending on the intended application (in vitro or in vivo) or the individual being treated and the condition of the disease (eg, the individual's weight, age, and sex), the severity of the condition, the mode of administration, and the like, which may be Those skilled in the art will readily decide. The term also applies to doses that induce a particular response in a target cell (eg, subtraction) Special platelet adhesion and/or cell migration) or specific reactions in such cells in specific chambers of the body (eg, lymph nodes or bone marrow carrying tumors, microenvironment of solid tumors, or active sites of autoimmune diseases and inflammatory reaction sites) Dosage. The dosage will vary depending on the particular compound and dosage form chosen, the administration configuration employed, whether the compound is administered in combination with other compounds, the time course of administration, the tissue to be administered, and the physiological delivery system in which the compound is administered.

The term "therapeutic effect" as used herein encompasses therapeutic and/or prophylactic benefits as described above. Prophylactic effects include delaying or eliminating the appearance of a disease or condition; delaying or eliminating the onset of a disease or condition; slowing, stopping or reversing the progression of the disease or condition, or any combination of these.

The term "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid. , mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Salt-derived organic bases include, for example, primary, secondary, and tertiary amines, substituted amines (which include naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Special Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium and magnesium salts.

The pharmaceutically acceptable carrier, or pharmaceutically acceptable excipient, is intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and agents for the active materials is well known in the art. The use of such media and agents in the therapeutic compositions of the present invention is encompassed by any of the conventional media or agents that are incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions described.

Prodrugs are intended to illustrate compounds which convert to the biologically active compounds described herein under physiological conditions or by solvolysis. Thus, the term pro-drug prodrug refers to a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs may be inactive when administered to an individual, but are converted to the active compound in vivo, for example by hydrolysis. Prodrug compounds often provide the advantage of solubility, histocompatibility or delayed release in mammalian organisms, as described, for example, in Bundgaard, Design of Prodrugs, Elsevier, 1985. The term "prodrug" is also intended to include any covalently bonded carrier which, when administered to an individual, releases the active compound in vivo. Prodrugs of the active compounds as described herein can be prepared by modifying the functional groups present in the active compound in such a manner that the modifications are cleaved by conventional procedures or in vivo to give the active parent compound. Prodrugs include, for example, compounds in which a hydroxy, amine or sulfhydryl group is bonded to any group, and when a prodrug of the active compound is administered to a mammalian subject, the bond cleaves to form a free form, respectively. Hydroxyl, free amine or free sulfhydryl. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols in the active compounds, various ester derivatives of carboxylic acids, or amine amines, mesamines of amine functional groups. And benzamide derivatives.

When used herein to describe, for example, physical or chemical properties, such as molecular weight or chemical formula, it is intended to include all combinations and subcombinations of the scope and the particular embodiments. When reference is made to a numerical or numerical range, the use of the term "about" means that the numerical or numerical range recited is an approximation of the range of experimental variability (or within the range of statistical experimental error), and thus the numerical or numerical range may The change is, for example, between 1% and 15% of the range of numbers or numbers.

〝alkyl〞 refers to a linear or branched hydrocarbon group having from 1 to 10 carbon atoms (for example, (C ₁ - ₁₀ ) alkyl or C ₁ -) which consists solely of carbon and hydrogen atoms and does not contain unsaturation. C ₁₀ alkyl). Whenever it appears herein, a numerical range (such as 〝1 to 10〞) means every integer within a given range, for example 〝1 to 10 carbon atoms 〞 means that the alkyl group can be 1 carbon atom, 2 The carbon atom, the three carbon atoms, and the like up to and including 10 carbon atoms, although the definition is also intended to cover the term "indenyl" which does not explicitly dictate the numerical range. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, isobutyl, tert-butyl, pentyl, Isoamyl, neopentyl, hexyl, heptyl, octyl, decyl and decyl. The alkyl moiety can be attached to the remainder of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl , n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl. Unless otherwise specifically stated in the specification, an alkyl group is optionally substituted with one or more of the following substituents independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

〝alkylaryl 〞 refers to -(alkyl)aryl, wherein aryl and alkyl are as disclosed herein, and are optionally adapted to one of the substituents of the aryl group and the alkyl group, respectively. Replaced by many.

A nonylheteroaryl hydrazone refers to an -(alkyl)heteroaryl group, wherein the heteroaryl and alkyl groups are as disclosed herein, and are optionally employed in the substituents of the aryl group and the alkyl group, respectively. Replaced by one or more.

A nonylheterocycloalkylalkyl group refers to an -(alkyl)heterocyclyl group, wherein alkyl and heterocycloalkyl are as disclosed herein, and are optionally adapted to the heterocycloalkyl and alkyl groups, respectively. One or more of the substituents are substituted.

The oxime olefin moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and the decyne oxime moiety is composed of at least two carbon atoms and at least one carbon-carbon bond. Group. alkyl The moiety (whether saturated or unsaturated) may be branched, straight chain or cyclic.

Terpene alkenyl refers to a linear or branched hydrocarbon group (ie, (C _2-10 ) alkenyl group) consisting of only carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 10 carbon atoms. C _2-10 alkenyl). Whenever it appears herein, the numerical range (such as 〝2 to 10〞) refers to each integer within a given range, for example 〝2 to 10 carbon atoms 〞 means that the alkenyl group can be 2 carbon atoms, 3 The carbon atoms are up to and including up to 10 carbon atoms. The alkenyl moiety can be attached to the remainder of the molecule by a single bond, such as a vinyl group (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pentane 1-enyl and pentane-1,4-dienyl. Unless otherwise specifically stated in the specification, alkenyl is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl. , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ ,- C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl , fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Terpene-cycloalkylindole refers to an -(alkenyl)cycloalkyl group, wherein alkenyl and cycloalkyl are as disclosed herein, and are optionally adapted to the substitution of alkenyl and cycloalkyl, respectively. One or more of the bases are replaced.

〝 alkynyl hydrazine refers to a linear or branched hydrocarbon group having from at least one reference bond and having from 2 to 10 carbon atoms (ie (C _2-10 ) alkynyl group and C) consisting of only carbon and hydrogen atoms. _2-10 alkynyl). Whenever it appears herein, the numerical range (such as 〝2 to 10〞) refers to each integer within a given range, for example 〝2 to 10 carbon atoms 〞 means that the alkynyl group can be 2 carbon atoms, 3 The carbon atoms are up to and including up to 10 carbon atoms. An alkynyl group can be attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless otherwise specifically stated in the specification, an alkynyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl. , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ ,- C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl , fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

〝 alkynyl-cycloalkyl hydrazine refers to -(alkynyl)cycloalkyl, wherein alkynyl and cycloalkyl are as disclosed herein, and which are optionally substituted for the alkynyl and cycloalkyl, respectively. One or more of the bases are replaced.

〝Formaldehyde oxime refers to the -(C=O)H group.

〝Carboxylium refers to the -(C=O)OH group.

Indole cyano is a -CN group.

Anthracenylcycloindole refers to a monocyclic or polycyclic group containing only carbon and hydrogen and which may be saturated or partially unsaturated. The cycloalkyl group includes a group having from 3 to 10 ring atoms (that is, a (C _3-10 ) cycloalkyl group and a C _3-10 cycloalkyl group). Whenever it appears herein, a numerical range (such as 〝3 to 10〞) means every integer within a given range, for example 〝3 to 10 carbon atoms 〞 means that the cycloalkyl group can be from 3 carbon atoms, etc. Up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, Cyclodecyl, thiol and the like. Unless otherwise specifically stated in the specification, a cycloalkyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane Base, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

〝Cycloalkyl-alkenyl hydrazine refers to -(cycloalkyl)alkenyl, wherein cycloalkyl and alkenyl are as disclosed herein, and are optionally adapted to the substitution of a cycloalkyl and an alkenyl group, respectively. One or more of the bases are replaced.

〝Cycloalkyl-heterocycloalkyl hydrazine refers to -(cycloalkyl)heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are as disclosed herein, and are optionally adapted to cycloalkyl and One or more of the substituents of the heterocycloalkyl group are substituted.

〝Cycloalkyl-heteroaryl hydrazine refers to a -(cycloalkyl)heteroaryl group, wherein cycloalkyl and heteroaryl are as disclosed herein, and are optionally adapted to cycloalkyl and heteroaryl, respectively. One or more of the substituents are substituted.

The term "decyloxy" refers to the group -O-alkyl, which is attached to the parent structure via oxygen, including straight, branched or cyclic configurations of from 1 to 8 carbon atoms and combinations thereof. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclohexyloxy. The fluorene alkoxy alkoxy group means an alkoxy group having 1 to 6 carbon atoms.

The term "substituted alkoxy" refers to an alkoxy group in which an alkyl component is substituted (i.e., -O-(substituted alkyl)). Unless otherwise specifically stated in the specification, the alkyl portion of the alkoxy group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl. ,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane , -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C( O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S (O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independent It is hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term "decyloxycarbonyl" refers to a radical of the formula (alkoxy)(C=O)- linked via a carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus, (C _1-6 )alkoxycarbonyl is an alkoxy group having from 1 to 6 carbon atoms which is bonded to a carbonyl linking group via its oxygen. The fluorene alkoxycarbonyl hydrazine refers to an alkoxycarbonyl group in which the alkoxy group is a lower alkoxy group.

The term "substituted alkoxycarbonyl" refers to a group (substituted alkyl)-OC(O)- wherein the group is attached to the parent structure via a carbonyl function. Unless otherwise specifically stated in the specification, the alkyl portion of the alkoxycarbonyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkane , heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl矽, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N( R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C (O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), - S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^a Independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Mercapto group refers to the group (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C ( O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure via a carbonyl function. If the R group is heteroaryl or heterocycloalkyl, the heterocyclic or chain atom contributes to the total number of chains or ring atoms. Unless otherwise specifically stated in the specification, the alkyl, aryl or heteroaryl portion of the indenyl group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitrate , trimethyldecane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC (O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N (R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 Or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , Wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or hetero Arylalkyl.

An oxime oxime refers to a R(C=O)O- group, wherein 〝R〞 is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl as described herein. If the R group is heteroaryl or heterocycloalkyl, the heterocyclic or chain atom contributes to the total number of chains or ring atoms. Unless otherwise specifically stated in the specification, 醯R〞 of the methoxy group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl ,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane , -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C( O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S (O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independent It is hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Amidoxime or amidoxime refers to a -N(R ^a ) ₂ group, wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aryl Alkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless otherwise specifically stated in the specification. When the -N(R ^a ) ₂ group has two R ^a substituents other than hydrogen, the substituents may be combined with a nitrogen atom to form a 4, 5, 6 or 7 membered ring. For example, -N(R ^a ) _{2 is} intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise specifically stated in the specification, the amine group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ ,- C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl , fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term "substituted amino group" also refers to the N-oxides of the groups -NHR ^d and NR ^d R ^d as described above, respectively. The N-oxide can be prepared by treating the corresponding amine group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

Amidoxime or guanamine oxime refers to a chemical moiety having the formula -C(O)N(R) ₂ or -NHC(O)R, wherein R is selected from the group consisting of hydrogen, alkane The group, the cycloalkyl group, the aryl group, the heteroaryl group (bonded via a ring carbon) and the heteroalicyclic group (bonded via a ring carbon), each of which can be optionally substituted. 5, 6 or 7-membered ring is formed together Amides of -N (R) of the ₂ R ₂ with the nitrogen may be optionally attached. Unless otherwise specifically stated in the specification, the guanamine group is optionally independently one of the substituents for alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl groups as described herein or Replaced by many. The guanamine can be an amino acid or peptide molecule attached to a compound disclosed herein to form a prodrug. The procedures and specific groups for making such guanamines are known to those skilled in the art and can be readily found in sources such as Greene et al., Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons, 2007, the entire contents of which is incorporated herein by reference.

〝Aromatic 〝 or 〝 aryl 〞 or 〝Ar〞 means an aromatic group having 6 to 10 ring atoms (for example, (C _6-10 ) aromatic or C _6-10 aromatic or (C _6-10) An aryl or C _6-10 aryl group having at least one ring having a conjugated pi electron system which is a carbocyclic ring (e.g., phenyl, anthryl and naphthyl). A divalent group formed from a substituted benzene derivative and having a free valence on a ring atom is designated as a substituted phenyl group. A divalent group derived from a monovalent polycyclic hydrocarbon group terminated by a fluorenyl-yl (-yl) fluorene group by removing a hydrogen atom from a carbon atom having a free valence is a fluorene group (-idene). It is named by adding the name of the corresponding monovalent group, for example, a naphthyl group having two points of attachment is referred to as a naphthylene group. Whenever it appears herein, the numerical range (such as 〝6 to 10〞) refers to each integer within a given range, for example 〝6 to 10 ring atoms 〞 means that the aryl group can be 6 ring atoms, 7 A ring atom is composed up to and including 10 ring atoms. The term includes monocyclic or fused ring polycyclic (ie, a ring that shares an adjacent ring atom pair). Unless otherwise specifically stated in the specification, the aryl moiety is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane Base, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

An aralkylalkyl or arylarylalkyl group refers to an (aryl)alkyl- group, wherein the aryl and alkyl groups are as disclosed herein, and are optionally employed as described above for the aryl group and the alkyl group, respectively. One or more of the substituents are substituted.

An oxime ester is a chemical group of the formula -COOR wherein the R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (via ring carbon bonding) and heteroalicyclic (via ring carbon bonding). The procedures for making esters and the specific groups are known to those skilled in the art and can be readily found in sources such as Greene et al., Protective Groups in Organic Synthesis, 4th ^rd Ed., John Wiley & Sons, 2007. Unless otherwise specifically stated in the specification, the ester group is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane Base, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl decane, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N( R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkane A fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl group.

A fluoroalkylalkyl group means an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl. Base, 1-fluoromethyl-2-fluoroethyl and the like. The alkyl portion of the fluoroalkyl group can be optionally substituted as defined above for the alkyl group.

The hydrazine hydrazine, the hydrazine halide or the other selected hydrazine halogen is intended to be referred to as fluorine, chlorine, bromine or iodine. The term "haloalkyl", fluorenylalkenyl, fluorenyl alkynyl and fluorenyl alkoxy including alkyl, alkenyl, alkynyl and alkoxy substituted by one or more halo groups or combinations thereof Base structure. For example, the terms fluorinated alkyl fluorene and fluorinated alkoxy fluorene each include a haloalkyl group and a haloalkoxy group in which the halogen group is fluorine.

The deuterated alkyl anthracene, the deuterated alkenyl anthracene, and the alkynyl alkynyl group include an optionally substituted alkyl group, an alkenyl group, and an alkynyl group, and have one or more skeleton chain atoms selected from atoms other than carbon, For example, oxygen, nitrogen, sulfur, phosphorus or a combination thereof. A numerical range can be given, such as (C _1-4 )heteroalkyl or C _{1-4heteroalkyl} , which refers to the total chain length, which in this example is 4 atoms in length. Heteroalkyl groups may be substituted by one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl , heteroarylalkyl, hydroxy, halo, cyano, nitro, keto, thioketo, trimethyldecyl, OR ^a , -SR ^a , -OC(O)-R ^a , -N ( R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N( _{^{R a) 2, -N (R}} a) S (O) t R a ( where t is 1 or 2), - S (O) t oR a ( wherein t is 1 or 2), - S (O) t N(R ^a ) ₂ (wherein t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl Alkyl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Doped alkylaryl hydrazine refers to a -(heteroalkyl)aryl group, wherein heteroalkyl and aryl are as disclosed herein, and are optionally adapted to the substituents of heteroalkyl and aryl, respectively. One or more of them are replaced.

Deuterated alkylheteroaryl is a -(heteroalkyl)heteroaryl group, wherein heteroalkyl and heteroaryl are as disclosed herein, and are optionally adapted to heteroalkyl and heteroaryl, respectively. One or more of the substituents are substituted.

Doped alkylheterocycloalkyl hydrazine is a -(heteroalkyl)heterocycloalkyl group, wherein heteroalkyl and heterocycloalkyl are as disclosed herein, and are optionally adapted to heteroalkyl and hetero, respectively. One or more of the substituents of the cycloalkyl group Replaced by.

Doped alkylcycloalkyl hydrazine refers to a -(heteroalkyl)cycloalkyl group, wherein heteroalkyl and cycloalkyl are as disclosed herein, and are optionally adapted to heteroalkyl and cycloalkyl, respectively. One or more of the substituents are substituted.

A doped aryl hydrazine or a doped aromatic hydrazine or hydrazine HetAr 〞 refers to a 5 to 18 membered aromatic group (eg, (C _5-18 )heteroaryl or C _{5-18heteroaryl} ), which includes one or A plurality of ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems. Whenever it appears herein, a numerical range (such as 〝5 to 18 〞) refers to each integer within a given range, for example 〝5 to 18 ring atoms 〞 means that the heteroaryl group can be 5 ring atoms, The 6 ring atoms are composed up to and including 18 ring atoms. A divalent group derived from a monovalent heteroaryl group terminated by a fluorenyl-yl (-yl) fluorene by removing a hydrogen atom from an atom having a free valence is added by a fluorene group (-idene) Named in the name of the corresponding monovalent group, for example, a pyridyl group having two points of attachment is referred to as a pyridylene group. The N-containing doped aromatic fluorene or deuterated aryl fluorene moiety refers to an aromatic group in which at least one of the skeleton atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group can be fused or unfused. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms, if any, are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule via any atom of the ring. Examples of heteroaryl groups include, but are not limited to, aziridine, acridinyl, benzimidazolyl, benzindenyl, 1,3-benzodioxan, benzofuranyl, benzoxazolyl, benzene And [d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxoheptyl, benzo[b][1,4] Base, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxanyl, benzodioxanyl, benzoxazolyl, benzene And pyranyl, benzopyranone, benzofuranyl, benzofuranone, benzofurazyl, benzothiazolyl, benzothienyl (benzothiophenyl) Benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-α]pyridinyl, oxazolyl, porphyrinyl, cyclopentyl Dienyl[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h Quinazolinyl, 5,6-dihydrobenzo[h]porphyrinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptadieno[1,2-c]indole , dibenzofuranyl, dibenzothiophenyl, furyl, furazyl, furanone, furo[3,2-c]pyridyl, 5,6,7,8,9,10-hexa Hydrocyclooctadienyl [d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctadieno[d]fluorene ,5,6,7,8,9,10-hexahydrocyclooctadieno[d]pyridyl, isothiazolyl, imidazolyl, oxazolyl, indolyl, carbazolyl, isodecyl , indanyl, isoindoline, isoquinolyl, anthracene Base, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinyl, oxadiazole, 2 - Ketoazinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H -pyrrolyl, brown Thiophene Base Base , pteridinyl, fluorenyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyridine [3,4-d]pyrimidinyl, pyridyl Base, pyrimidinyl, oxime , pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7 , 8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptadieno[4,5]thieno[ 2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]indole Base, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, tri , thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and thiophenyl (ie thienyl) ). Unless otherwise specifically stated in the specification, the heteroaryl moiety is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle. Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, keto, thioketo, trimethyldecyl, -OR ^a , - SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C (O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl, Fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridyl N-oxide.

Doped arylalkyl hydrazine refers to a moiety having an aryl moiety as described herein attached to an alkylene moiety as described herein, wherein the remainder of the molecule is attached via an alkylene group.

〝Heterocycloalkyl hydrazine refers to a stable 3 to 18 membered non-aromatic ring group containing from 2 to 12 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, the numerical range (such as 〝3 to 18〞) refers to each integer within a given range, for example, 〝3 to 18 ring atoms 〞 means that the heterocycloalkyl group can be composed of 3 ring atoms. 4 ring atoms, etc. up to and including 18 ring atoms. Unless otherwise specifically stated in the specification, heterocycloalkyl groups are monocyclic, bicyclic, tricyclic or tetracyclic ring systems which may include fused or bridged ring systems. The hetero atom in the heterocycloalkyl group can be optionally oxidized. One or more nitrogen atoms, if any, are optionally quaternized. Heterocycloalkyl groups are partially saturated or fully saturated. A heterocycloalkyl group can be attached to the remainder of the molecule via any atom of the ring. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolane, thienyl [1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, Isoxazolidinyl, morpholinyl, octahydroindenyl, octahydroisodecyl, 2-ketopipe Base, 2-ketopiperidinyl, 2-ketopyrrolidinyl, oxazolidinyl, piperidinyl, piperidine , 4-piperidinone, pyrrolidinyl, pyrazolyl, acridinyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholine Base, 1-keto-thiomorpholinyl and 1,1-dionethiomorpholinyl. Unless otherwise specifically stated in the specification, a heterocycloalkyl moiety is optionally substituted with one or more substituents independently of the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, keto, thioketo, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ ,- C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl , fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

〝Heterocycloalkyl fluorene also includes a bicyclic ring system in which one non-aromatic ring (generally having 3 to 7 ring atoms) contains, in addition to 1 to 3, heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, and the foregoing At least 2 carbon atoms other than a combination of at least one of the heteroatoms; and the other ring (generally having 3 to 7 ring atoms) optionally contain 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen. And not for the aromatics.

Part of the oxime refers to a specific segment or functional group of the molecule. The chemical moiety is typically a recognized chemical entity that is embedded or attached to the molecule.

Nitrosoguanidine refers to the -NO ₂ group.

Anthraquinone refers to an -O- group.

Anthrone-based oxime refers to the =0 group.

The oxime isomers are compounds having the same molecular formula. The oxime stereoisomers are isomers that differ only in the arrangement of atoms in space - that is, have different stereochemical configurations. The 〝 mirror isomer is a pair of stereoisomers that are non-superimposable mirror images of each other. A pair of mirror image isomers in a 1:1 mixture is a racemic ruthenium mixture. The term 〝(±)〞 is used to calibrate the racemic mixture where appropriate. The non-image isomer is a stereoisomer having at least two asymmetric atoms but not mirror images of each other. Absolute stereochemistry is specified according to the Rahn S-system of Cahn-Ingold-Prelog. When the compound is a pure mirror image isomer, the stereochemistry of each palm carbon can be specified by (R) or (S). An isolated compound of unknown absolute configuration may depend on its direction of rotation of plane polarized light at the wavelength of the sodium D line (right Scaling or left-handed) and calibrating (+) or (-). Certain compounds as described herein contain one or more asymmetric centers and may therefore result in mirror image isomers, non-image isomers, and other stereoisoforms that may be defined by absolute stereochemistry as (R) or (S). Structure type. The chemical entities, pharmaceutical compositions and methods of the present invention are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The optically active (R)- and (S)-isomers can be prepared using palmitic synthetic components or palmitic reagents or isolated using conventional techniques. When a compound described herein contains an olefinic double bond or other geometrically asymmetric center and unless otherwise specified, it is intended that the compound include both E and Z geometric isomers.

As used herein, 〝image isomer purity 〞 refers to the relative amount of a particular mirror image isomer relative to other smectomers, expressed as a percentage. For example, if a compound having a (R)- or (S)-isomer configuration is present as a racemic mixture, the purity of the mirror image is about (R)- or (S)-isomer 50%. If the compound has an isomeric form that exceeds other forms, such as 80% of the (S)-isomer and 20% of the (R)-isomer, the mirror image isomer purity of the compound is related to (S)- The structure type is 80%. The mirror image isomer purity of a compound can be determined in a number of ways known in the art including, but not limited to, chromatography using a palmitic carrier, optical rotation measurements of polarized light rotation, nuclear magnetic resonance spectroscopy using a palm displacement reagent (this Reagents include, but are not limited to, lanthanides containing a palm compound or Pirkle's alcohol, or compounds derived using a palm compound such as Mosher acid, followed by chromatography or Nuclear magnetic resonance spectroscopy.

The term "enriched enantiomers" and "non-racemic" as used herein means that the weight percent of one of the mirror image isomers is greater than the one of the image isomers in the control mixture of the racemic composition. A composition (for example, greater than 1:1 by weight) of the composition. For example, an enriched mirror-isomerized formulation of (S)-mirrranomer is meant to have greater than 50% by weight (such as at least 75% by weight, such as at least 80% by weight) relative to the (R)-mirroromer. A formulation of a compound of (S)-mirroromer. In some embodiments, the enrichment can be substantially greater than 80% by weight, providing a formulation in which the quinone is substantially enriched with fluorene isomerism 〝 or 〝 substantially non-racemic oxime, which refers to isomerism relative to other mirrors. And a formulation having at least 85% by weight (such as at least 90% by weight or such as at least 95% by weight) of a composition of one of the mirror image isomers. The term "enriched enantiomers" and "non-racemic" as used herein means that the weight percent of one of the mirror image isomers is greater than the one of the image isomers in the control mixture of the racemic composition. Amount of composition. The term "mirrible isomerism" pure oxime or quinone substantially mirror image isomerism pure lanthanum refers to a composition comprising at least 98% of a single mirror image isomer and less than 2% of the opposite mirror image isomer.

In a preferred embodiment, the enriched mirror image isomer has a potency with respect to a therapeutic effect per unit mass greater than a racemic mixture of the composition. The mirror image isomers may be separated from the mixture by methods known to those skilled in the art, including palm oil high pressure liquid chromatography (HPLC) and the formation and crystallization of palm salts; or preferred mirror images. Isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley) Interscience, New York, 1981); Stereochemistry of Carbon Compounds by Eliel (McGraw-Hill, NY, 1962); and Stereochemistry of Organic Compounds by Eliel and Wilen (Wiley-Interscience, New York, 1994).

The oxime tautomers are structurally different isomers which are converted into each other by tautomerization. The oxime isomerization oxime is an isomerized form and includes proton transfer or proton shift tautomerization, which is considered to be a subgroup of acid-base chemistry. Proton transfer tautomerization 〞 or 〝 proton displacement tautomerization 〞 involves a proton transfer accompanied by a bond-level change in which a single bond is exchanged with an adjacent double bond. The chemical equilibrium of the tautomers can be achieved when tautomerization is feasible (eg, in solution). An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of a pentane-2,4-dione with a 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol with a pyridine-4(1H)-one tautomer.

The group referred to by hydrazine may be attached to one or more groups, radicals or additional moieties, individually and independently selected, for example, from the group consisting of fluorenyl, alkyl, alkylaryl, cycloalkyl, aryl Alkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, halo, carbonyl, Ester, thiocarbonyl, isocyanate group, thiocyanate group, isothiocyanate group, nitro group, keto group, perhaloalkyl group, perfluoroalkyl group, phosphate group, thiol group, sub Sulfonyl, sulfonyl, sulfonyl, sulfoxyl, sulfonic acid groups, Urea and amine groups, including mono- and disubstituted amine groups and their protected derivatives. Substituents may be substituted, for example, a cycloalkyl substituent may have a halide substituent on one or more of its ring carbons. The term "arbitrarily substituted" means optionally substituted at a particular group, radical or moiety.

Sulfanyl 〞 refers to -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and a group of -S-(optionally substituted heterocycloalkyl).

〝 sulfinyl hydrazine refers to -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino group), - S(O)-(optionally substituted aryl), -S(O)-(optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl) Group.

Sulfosyl hydrazine is meant to include -S(O ₂ )-H, -S(O ₂ )-(optionally substituted alkyl), -S(O ₂ )-(optionally substituted amino group) , -S(O ₂ )-(optionally substituted aryl), -S(O ₂ )-(optionally substituted heteroaryl) and -S(O ₂ )- (optionally substituted) a group of a cycloalkyl group.

Sulfonamidyl oxime or sulfonamido oxime refers to a -S(=O) ₂ -NRR group, wherein each R system is independently selected from the group consisting of hydrogen , alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and heteroalicyclic (bonded via a ring carbon). The R groups in the -NRR of -S(=O) ₂ -NRR may form a 4, 5, 6 or 7 membered ring together with the nitrogen to which they are attached. The sulfonamide group is optionally substituted with one or more of the substituents described for the alkyl group, the cycloalkyl group, the aryl group, and the heteroaryl group, respectively.

〝 碸 碸 〞 refers to the -S(=O) ₂ OH group.

"Sulfonic acid group" refers to -S (= O) ₂ -OR group, wherein the group R selected from the group consisting of consisting of: alkyl, cycloalkyl, aryl, heteroaryl (via a ring carbon bond And a heteroalicyclic group (bonded via a ring carbon). The sulfonic acid group is optionally substituted on R by one or more of the substituents described for the alkyl group, the cycloalkyl group, the aryl group, and the heteroaryl group, respectively.

The compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs of the compounds, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates) ), configuration polymorphs and amorphous forms, and mixtures thereof. The crystalline form 〞 and 〝 polymorphs are intended to include all crystalline forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including Anhydrous), conformational polymorphs and mixtures thereof. By hydrazine hydrate is meant a compound that is physically associated with one or more pharmaceutically acceptable solvent molecules. Hydrazine hydrate refers to a compound that is physically associated with one or more water molecules.

The term 〝QD〞, 〝qd〞 or 〝q.d.〞 means once a day, once a day or once a day. The term 〝BID〞, 〝bid〞 or 〝b.i.d.〞 means twice daily, twice a day or twice a day. The term 〝TID〞, 〝tid〞 or 〝t.i.d.〞 means three times a day, three times a day or three times a day. The term 〝QID〞, 〝qid〞 or 〝q.i.d.〞 means four times a day, four times a day or four times a day.

BTK inhibitor

BTK inhibitors can be any BTK known in the art preparation. It is in particular one of the BTK inhibitors described in more detail in the following paragraphs.

In one embodiment, the BTK inhibitor is a compound of formula (I): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, wherein: X is CH, N, O or S; Y is C(R ₆ ), N, O or S; Z is CH, N or a bond; A is CH or N; B ₁ is N or C(R ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or C(R ₉ ); B ₄ is N or C(R ₁₀ ); R ₁ is R ₁₁ C(=O), R ₁₂ S(=O), R ₁₃ S(=O) ₂ or optionally substituted by R ₁₄ (C _1-6 ) alkane R ₂ is H, (C _1-3 )alkyl or (C _3-7 )cycloalkyl; R ₃ is H, (C _1-6 )alkyl or (C _3-7 )cycloalkyl) Or R ₂ and R ₃ together with the N and C atoms to which they are attached form one or more fluoro, hydroxy, (C _1-3 )alkyl, (C _1-3 ) alkoxy or keto groups optionally Substituted (C _3-7 )heterocycloalkyl; R ₄ is H or (C _1-3 )alkyl; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _{1- 3} ) alkoxy, (C _3-6 )cycloalkyl, any of which is optionally substituted by one or more halogens; or R ₅ is (C _6-10 )aryl or (C _2-6 a heterocycloalkyl group; R ₆ is H or (C _1-3 )alkyl; or R ₅ and R ₆ together may form a (C _3-7 )cycloalkenyl group or a (C _2-6 )heterocyclenyl group, each are optionally substituted by (C _1-3) alkyl or substituted with one or more halo; R ₇ is H Halo, CF _3, (C _1-3) alkyl or (C _1-3) alkoxy; R ₈ is H, halogen, CF _3, (C _1-3) alkyl or (C _1-3) alkoxy An oxy group; or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 ) aryl group or a (C _1-9 )heteroaryl group; R ₉ is H, halogen, (C _1-3 ) An alkyl group or a (C _1-3 ) alkoxy group; R ₁₀ is H, a halogen, a (C _1-3 ) alkyl group or a (C _1-3 ) alkoxy group; and R _{11 is} independently selected from the group consisting of the following: Group: (C _1-6 )alkyl, (C _2-6 )alkenyl and (C _2-6 )alkynyl, wherein each alkyl, alkenyl or alkynyl group is optionally optionally one or more selected from the group consisting of Substituents substituted for the group consisting of: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amine, bis[(C _{1- 4} ) an alkyl]amino group, a (C _1-3 ) alkoxy group, a (C _3-7 ) cycloalkoxy group, a (C _6-10 ) aryl group, and a (C _3-7 )heterocycloalkyl group; R ₁₁ is (C _1-3 )alkyl-C(O)-S-(C _1-3 )alkyl; or R ₁₁ is optionally one or more selected from the group consisting of halogen or cyano a substituent substituted with a (C _1-5 )heteroaryl; R ₁₂ and R _{13 are} independently selected from the group consisting of: (C _2-6 )alkenyl or (C _2-6 )alkynyl, Randomly pass one or One selected from the group consisting of consisting of the following substituents: hydroxy, (C _1-4) alkyl, (C _3-7) cycloalkyl, [(C _1-4) alkyl] amino, di [ (C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl and (C _3-7 )heterocyclic An alkyl group; or a (C _1-5 )heteroaryl group optionally substituted with one or more substituents selected from the group consisting of halogen and cyano; and R _{14 are} independently selected from the group consisting of Group: halogen, cyano, (C _2-6 )alkenyl and (C _2-6 )alkynyl, both optionally substituted by one or more substituents selected from the group consisting of: hydroxy, ( C _1-4 )alkyl, (C _3-7 )cycloalkyl, (C _1-4 )alkylamino, bis[(C _1-4 )alkyl]amino, (C _1-3 ) alkane Oxyl, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, (C _1-5 )heteroaryl and (C _3-7 )heterocycloalkyl; prerequisites: X 0, 2 atoms in Y, Z may be heteroatoms at the same time; when one atom selected from X, Y is O or S, Z is a bond, and other atoms selected from X, Y may not be O or S; When Z is C or N, then Y is C(R ₆ ) or N, and X is C or N; among B ₁ , B ₂ , B ₃ and B ₄ 0 to 2 atoms are N; the term used has the following meaning: (C _1-2 )alkyl means an alkyl group having 1 to 2 carbon atoms which is a methyl group or an ethyl group (C _1-3) And alkyl means a branched or unbranched alkyl group having 1 to 3 carbon atoms which is methyl, ethyl, propyl or isopropyl; (C _1-4 )alkyl means 1- a branched or unbranched alkyl group of 4 carbon atoms which is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl and tert-butyl to (C _{1 -3} ) an alkyl group; (C _1-5 )alkyl means a branched or unbranched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl The base group, isobutyl group, second butyl group, tert-butyl group, pentyl group and isopentyl group are preferably a (C _1-4 ) alkyl group. (C _1-6 )alkyl means a branched or unbranched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or Amyl and n-hexyl. Preferred is (C _1-5 )alkyl, preferably (C _1-4 )alkyl; (C _1-2 )alkoxy means alkoxy having 1-2 carbon atoms, alkyl moiety Has the same meaning as previously defined; (C _1-3 ) alkoxy means an alkoxy group having 1 to 3 carbon atoms, and the alkyl moiety has the same meaning as previously defined. The (C _1-2 ) alkoxy group is preferred; the (C _1-4 ) alkoxy group means an alkoxy group having 1 to 4 carbon atoms, and the alkyl moiety has the same meaning as previously defined. Preferably, the (C _1-3 ) alkoxy group is the (C _1-2 ) alkoxy group; the (C _2-4 ) alkenyl group means a branched or unbranched chain having 2 to 4 carbon atoms. An alkenyl group such as a vinyl group, a 2-propenyl group, an isobutenyl group or a 2-butenyl group; (C _2-6 )alkenyl means a branched or unbranched alkenyl group having 2 to 6 carbon atoms, such as ethylene a 2-butenyl group and a n-pentenyl group, preferably (C _2-4 )alkenyl; (C _2-4 ) alkynyl means a branched or unbranched alkynyl group having 2 to 4 carbon atoms , such as ethynyl, 2-propynyl or 2-butynyl; (C _2-6 )alkynyl means a branched or unbranched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propyne A group, n-butynyl, n-pentynyl, isopenynyl, isohexynyl or n-hexynyl. Preferred is (C _2-4 )alkynyl; (C _3-6 )cycloalkyl means cycloalkyl having 3 to 6 carbon atoms which is cyclopropyl, cyclobutyl, cyclopentyl or cyclic (C _3-7 )cycloalkyl means a cycloalkyl group having 3 to 7 carbon atoms which is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group; (C _{2- 6} ) Heterocycloalkyl means a heterocycloalkyl group having 2 to 6 carbon atoms (preferably 3-5 carbon atoms) and one or two hetero atoms selected from N, O and/or S, It may be attached via a hetero atom or a carbon atom which may be employed; preferred heteroatoms are N or O; it is also preferably piperidine, morpholine, pyrrolidine and piperazine. The most preferred (C _2-6 )heterocycloalkyl group is pyrrolidine; the heterocycloalkyl group can be attached via a hetero atom as possible; (C _3-7 )heterocycloalkyl means having 3 to 7 carbon atoms (preferably 3-5 carbon atoms) and one or two heterocycloalkyl groups selected from heteroatoms of N, O and/or S. Preferred heteroatoms are N or O; preferred (C _3-7 )heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more preferably (C _3-7 )heterocycloalkyl is piperidine, morpholine and pyrrolidine; and heterocycloalkyl can be linked via a possible hetero atom; (C _3-7 )cycloalkoxy means via ring carbon An atom is bonded to a cycloalkyl group having 3 to 7 carbon atoms of the outer epoxy atom, the cycloalkyl group having the same meaning as previously defined; (C _6-10 ) aryl means having 6 to 10 carbon atoms An aromatic hydrocarbon group such as a phenyl group, a naphthyl group, a tetrahydronaphthyl group or a fluorenyl group; preferably a (C _6-10 ) aryl group is a phenyl group; (C _1-5 ) a heteroaryl group means having 1 to 5 a substituted or unsubstituted aromatic group of a carbon atom and 1 to 4 hetero atoms selected from N, O and/or S; (C _1-5 )heteroaryl optionally substituted; preferred (C _1-5 )heteroaryl is tetrazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, tri More preferably, the (C _1-5 )heteroaryl group is a pyrimidinyl group; the (C _1-9 )heteroaryl group means having 1 to 9 carbon atoms and 1 to 4 are selected from N a substituted or unsubstituted aromatic group of a hetero atom of O and/or S; a (C _1-9 )heteroaryl group optionally substituted; preferably a (C _1-9 )heteroaryl group is Quinoline, isoquinoline and anthracene; [(C _1-4 )alkyl]amino group means an amino group monosubstituted by an alkyl group having from 1 to 4 carbon atoms and having the same meaning as previously defined Preferred [(C _1-4 )alkyl]amino group is methylamino group; bis[(C _1-4 )alkyl]amino group means alkyl group substituted by alkyl group, each alkyl group Containing from 1 to 4 carbon atoms and having the same meaning as previously defined; preferred bis[(C _1-4 )alkyl]amino group is dimethylamino; halogen means fluorine, chlorine, bromine or iodine; C _1-3 )alkyl-C(O)-S-(C _1-3 )alkyl means alkyl-carbonyl-thio-alkyl, each alkyl group having 1 to 3 carbon atoms and having the same meaning as previously defined The same meaning; (C _3-7 )cycloalkenyl means a cycloalkenyl group having 3 to 7 carbon atoms (preferably 5 to 7 carbon atoms); preferably a (C _3-7 )cycloalkenyl group. Cyclopentenyl or cyclohexenyl; cyclohexene (C _2-6 ) Heterocyclenyl means a hetero atom having 2 to 6 carbon atoms (preferably 3-5 carbon atoms) and 1 hetero atom selected from N, O and/or S. Heterocyclenyl; preferred (C _2-6 )heterocyclenyl is oxycyclohexenyl and azacyclohexenyl.

In the above definition having a polyfunctional group, the point of attachment is on the last group.

In the definition of a substituent, when all of the alkyl hydrazines of the substituent are indicated as being optionally substituted, this also includes the alkyl portion of the alkoxy group.

A circle in the ring of formula (I) indicates that the ring is aromatic.

Depending on the ring formed, if nitrogen is present in X or Y, the nitrogen can carry hydrogen.

In a preferred embodiment, the BTK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: X is CH or S; Y is C(R ₆ ); Z is CH or a bond; Is CH; B ₁ is N or C(R ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or CH; B ₄ is N or CH; and R ₁ is R ₁₁ C(=O), R ₂ is (C _1-3 )alkyl; R ₃ is (C _1-3 )alkyl; or R ₂ and R ₃ together with the N and C atoms to which they are attached form a group selected from the group consisting of (C _3-7 )heterocycloalkyl ring: azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl optionally substituted with one or more fluorine, hydroxy, (C _1-3 ) alkane Substituted or substituted by (C _1-3 )alkoxy; R ₄ is H; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _1-3 )alkoxy, (C _{3 -6} ) a cycloalkyl group, or an alkyl group optionally substituted by one or more halogens; R ₆ is H or (C _1-3 )alkyl; R ₇ is H, halogen or (C _1-3 ) alkoxy R ₈ is H or (C _1-3 )alkyl; or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 )aryl or (C _1-9 )heteroaryl; R ₅ and R ₆ may together form a (C _3-7) cycloalkenyl or (C _2-6) heterocycloalkenyl group, each are optionally substituted by (C _1-3) alkyl or one or more halo Generation; R ₁₁ is independently selected from the group consisting of consisting of the following: (C _2-6) alkenyl and (C _2-6) alkynyl, wherein each alkenyl or alkynyl group optionally substituted by one or more selected from the group consisting of The substituents of the following group are substituted: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amine, bis[(C _{1 -4} )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl and (C _3-7 )heterocycloalkyl; It is a prerequisite that 0 to 2 of B ₁ , B ₂ , B ₃ and B ₄ are N.

In one embodiment of formula (I), B ₁ is C(R ₇ ); B ₂ is C(R ₈ ); B ₃ is C(R ₉ ); B ₄ is C(R ₁₀ ); R ₇ And R ₉ and R ₁₀ are each H; and R ₈ is hydrogen or methyl.

In one embodiment of formula (I), the ring system containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidinyl, indole Base, three Base, thiazolyl, oxazolyl and isoxazolyl.

In one embodiment of formula (I), the ring system containing X, Y and Z is selected from the group consisting of pyridyl, pyrimidinyl and indole base.

In one embodiment of formula (I), the ring system containing X, Y and Z is selected from the group consisting of pyridyl and pyrimidinyl.

In one embodiment of formula (I), the ring containing X, Y and Z is a pyridyl group.

In one embodiment of formula (I), R ₅ is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, and trifluoromethyl.

In an embodiment of formula (I), R ₅ is hydrogen.

In one embodiment of formula (I), R ₂ and R ₃ together form a heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, high. Piperidinyl and morpholinyl, such groups are optionally substituted with one or more of fluorine, hydroxy, (C _1-3 )alkyl and (C _1-3 )alkoxy.

In one embodiment of formula (I), R ₂ and R ₃ together form a heterocycloalkyl ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl.

In one embodiment of formula (I), R ₂ and R ₃ together form a pyrrolidinyl ring.

In an embodiment of formula (I), R _{1 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl or (C _2-6 )alkyne Each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _{1- 4} ) alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 ) aryl And (C _3-7 )heterocycloalkyl.

In one embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X is N; Y and Z are CH; R ₅ is CH ₃ ; A is N; R ₂ , R ₃ and R ₄ are H; and R ₁ is CO-CH ₃ .

In one embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X and Y are N; Z is CH; R ₅ is CH ₃ ; A is N; R ₂ , R ₃ and R ₄ are H; and R ₁ is CO-CH ₃ .

In one embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X and Y are N; Z is CH; R ₅ is CH ₃ ; A is CH; R ₂ and R ₃ together form a piperidinyl ring; R ₄ is H; and R ₁ is a CO-vinyl group.

In one embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X, Y and Z are CH; R ₅ is H; A is CH; and R ₂ is formed together with R ₃ Pyrrolidinyl ring; R ₄ is H; and R ₁ is CO-propynyl.

In one embodiment of formula (I), B ₁ , B ₂ , B ₃ and B ₄ are CH; X, Y and Z are CH; R ₅ is CH ₃ ; A is CH; R ₂ together with R ₃ A piperidinyl ring is formed; R ₄ is H; and R ₁ is a CO-propynyl group.

An implementation aspect, in formula (I) _{in, B 1, B 2, B} 3 and B4 is CH; X and Y is N; Z is CH; R ₅ is H; A is CH; R ₂ and R ₃ together A morpholinyl ring is formed; R ₄ is H; and R ₁ is a CO-vinyl group.

An implementation aspect, in formula (I) _{in, B 1, B 2, B} 3 and B ₄ is CH; X and Y is N; Z is CH; R ₅ is CH _3; A is CH; R ₂ and R ₃ together form a morpholinyl ring; R ₄ is H; and R ₁ is a CO-propynyl group.

In a preferred embodiment, the BTK inhibitor is a compound of formula (II): Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is (S)-4-(8-amino-3-(1-(but-2-yl)pyrrolidin-2-yl)imidazo[1, 5-a]pyridyl 1-yl)-N-(pyridin-2-yl)benzamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof.

In a preferred embodiment, the BTK inhibitor is a compound of formula (III): Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of formula (IV): Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of formula (V): Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of formula (VI): Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is a compound of formula (VII): Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of which is incorporated herein by reference.

In other embodiments, the BTK inhibitors include, but are not limited to, those compounds described in U.S. Patent Application Publication No. 2014/0155385 A1, the disclosure of each of each of which is hereby incorporated by reference.

In one embodiment, the BTK inhibitor is a compound of formula (VIII): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, wherein: X is CH, N, O or S; Y is C(R ₆ ), N, O or S; Z is CH, N or a bond; A is CH or N; B ₁ is N or C(R ₇ ); B ₂ is N or C(R ₈ ); B ₃ is N or C(R ₉ ); B ₄ is N or C(R ₁₀ ); R ₁ is R ₁₁ C(O), R ₁₂ S(O), R ₁₃ SO ₂ or (C _1-6 )alkyl optionally substituted by R ₁₄ ; R ₂ is H (C _1-3 )alkyl or (C _3-7 )cycloalkyl; R ₃ is H, (C _1-6 )alkyl or (C _3-7 )cycloalkyl; or R ₂ and R ₃ Together with their attached N and C atoms, they are optionally substituted by one or more fluorine, hydroxy, (C _1-3 )alkyl, (C _1-3 ) alkoxy or keto groups (C _3-7 a heterocycloalkyl group; R ₄ is H or (C _1-3 )alkyl; R ₅ is H, halogen, cyano, (C _1-4 )alkyl, (C _1-3 )alkoxy, ( C _3-6 )cycloalkyl; all alkyl groups of R ₅ are optionally substituted by one or more halogens; or R ₅ is (C _6-10 )aryl or (C _2-6 )heterocycloalkyl; ₆ is H or (C _1-3 )alkyl; or R ₅ and R ₆ together may form (C _3-7 )cycloalkenyl or (C _2-6 )heterocyclenyl; each optionally passes (C _1-3 ) an alkyl group or one or more halogen substitutions; R ₇ is H, halogen , CF ₃ , (C _1-3 )alkyl or (C _1-3 )alkoxy; R ₈ is H, halogen, CF ₃ , (C _1-3 )alkyl or (C _1-3 )alkoxy Or R ₇ and R ₈ together with the carbon atom to which they are attached form a (C _6-10 )aryl or (C _1-5 )heteroaryl; R ₉ is H, halo, (C _1-3 ) alkane Or (C _1-3 )alkoxy; R ₁₀ is H, halogen, (C _1-3 )alkyl or (C _1-3 )alkoxy; R _{11 is} independently selected from the group consisting of :(C _1-6 )alkyl, (C _2-6 )alkenyl and (C _2-6 )alkynyl, each alkyl, alkenyl or alkynyl optionally freely via one or more selected from the group consisting of Group substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino , (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl or (C _3-7 )heterocycloalkyl, or R ₁₁ is (C _{1- 3} ) an alkyl-C(O)-S-(C _1-3 )alkyl group; or R ₁₁ is optionally substituted by one or more groups selected from halogen or cyano groups (C _1-5 ) Aryl; R ₁₂ and R _{13 are} independently selected from the group consisting of: (C _2-6 )alkenyl or (C _2-6 )alkynyl, optionally arbitrarily selected from one or more selected from the group consisting of Group substitution: hydroxyl, (C _1-4 ) alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _{3 -7} ) cycloalkoxy, (C _6-10 ) aryl or (C _3-7 )heterocycloalkyl; or optionally substituted by one or more groups selected from halogen or cyano (C _1-5 )heteroaryl; R _{14 is} independently selected from the group consisting of halogen, cyano or (C _2-6 )alkenyl or (C _2-6 )alkynyl, the latter two optionally One or more groups selected from the group consisting of: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, di[(C _1-4 ) alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, (C _1-5 )heteroaryl or (C _3-7 )heterocycloalkyl; preconditions that - 0, 2, and 3 of X, Y, and Z may be heteroatoms at the same time; - when one atom selected from X, Y is O or S, then Z Is a bond, and other atoms selected from X, Y may not be O or S; - when Z is C or N, then Y is C(R ₆ ) or N, and X is C or N; - B ₁ , B ₂ , _{2 to 2} of B ₃ and B ₄ are N; the term used has the following meaning: (C _1-3 )alkyl means a branched or unbranched alkane having 1 to 3 carbon atoms base , which is methyl, ethyl, propyl or isopropyl; (C _1-4 )alkyl means a branched or unbranched alkyl group having 1 to 4 carbon atoms which is methyl or ethyl , propyl, isopropyl, butyl, isobutyl, t-butyl and t-butyl, preferably (C _1-3 )alkyl; (C _1-6 )alkyl means having 1- A branched or unbranched alkyl group of 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, n-pentyl and n-hexyl. Preferred is (C _1-5 )alkyl, preferably (C _1-4 )alkyl; (C _1-2 )alkoxy means alkoxy having 1-2 carbon atoms, alkyl moiety Has the same meaning as previously defined; (C _1-3 ) alkoxy means an alkoxy group having 1 to 3 carbon atoms, and the alkyl moiety has the same meaning as previously defined. Preferred is (C _1-2 ) alkoxy; (C _2-3 )alkenyl means alkenyl having 2 to 3 carbon atoms, such as vinyl or 2-propenyl; (C _2-4 ) ene Base means a branched or unbranched alkenyl group having 2 to 4 carbon atoms, such as a vinyl group, a 2-propenyl group, an isobutenyl group or a 2-butenyl group; and a (C _2-6 ) alkenyl group means having 2 a branched or unbranched alkenyl group of 6 to 6 carbon atoms such as a vinyl group, a 2-butenyl group and a n-pentenyl group, preferably a (C _2-4 ) alkenyl group, and a (C _2-3 ) alkene. Even more preferably; (C _2-4 ) alkynyl means a branched or unbranched alkynyl group having 2 to 4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl; _2-3 ) alkynyl means an alkynyl group having 2 to 3 carbon atoms, such as ethynyl or 2-propynyl; (C _2-6 )alkynyl means a branch having 2 to 6 carbon atoms or Non-branched alkynyl, such as ethynyl, propynyl, n-butynyl, n-pentynyl, isopenynyl, isohexynyl or n-hexynyl. Preferably, the (C _2-4 ) alkynyl group is more preferably a (C _2-3 ) alkynyl group; and the (C _3-6 ) cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, which is Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (C _3-7 )cycloalkyl means cycloalkyl having 3-7 carbon atoms which is cyclopropyl, cyclobutyl, cyclopentane Or a cyclohexyl group or a cycloheptyl group; (C _2-6 )heterocycloalkyl means having 2 to 6 carbon atoms (preferably 3-5 carbon atoms) and one or two selected from N, O and a heterocycloalkyl group of a hetero atom of S, which may be attached via a hetero atom or a carbon atom which may be employed; preferred heteroatoms are N or O; preferred groups are piperidine, morpholine, pyrrolidine and Piper The most preferred (C _2-6 )heterocycloalkyl group is pyrrolidine; and the heterocycloalkyl group can be attached via a hetero atom as possible; (C _3-7 )heterocycloalkyl means 3-7 carbons An atom (preferably 3-5 carbon atoms) and one or two heterocycloalkyl groups selected from heteroatoms of N, O and/or S. Preferred heteroatoms are N or O; preferred (C _3-7 )heterocycloalkyl is azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl; more preferably (C _3-7 )heterocycloalkyl is piperidine, morpholine and pyrrolidine; even more preferred are piperidine and pyrrolidine; and heterocycloalkyl can be linked via a hetero atom if feasible; (C _{3- 7} ) A cycloalkoxy means a cycloalkyl group having 3 to 7 carbon atoms bonded to an outer epoxy atom via a ring carbon atom, the cycloalkyl group having the same meaning as previously defined; (C _6-10 ) aryl Base means an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or anthracenyl; preferred (C _6-10 ) aryl is phenyl; (C _1-5 a heteroaryl group means a substituted or unsubstituted aromatic group having 1 to 5 carbon atoms and 1 to 4 hetero atoms selected from N, O and/or S; (C _1-5 ) The aryl group may be optionally substituted; preferred (C _1-5 )heteroaryl is tetrazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, tri a base, a thienyl or furyl group, and more preferably a (C _1-5 )heteroaryl group is a pyrimidinyl group; a [(C _1-4 )alkyl]amino group means an amino group monosubstituted by an alkyl group, the alkane The group contains 1 to 4 carbon atoms and has the same meaning as previously defined; preferred [(C _1-4 )alkyl]amino group is methylamino group; bis[(C _1-4 )alkyl]amino group An alkyl group substituted with an alkyl group, each alkyl group having 1 to 4 carbon atoms and having the same meaning as previously defined; preferred bis[(C _1-4 )alkyl]amino group is dimethyl Amine; halogen means fluorine, chlorine, bromine or iodine; (C _1-3 )alkyl-C(O)-S-(C _1-3 )alkyl means alkyl-carbonyl-sulfanyl-alkyl, Each alkyl group has 1 to 3 carbon atoms and has the same meaning as previously defined; (C _3-7 )cycloalkenyl means a cycloolefin having 3 to 7 carbon atoms, preferably 5 to 7 carbon atoms. Preferred (C _3-7 )cycloalkenyl is cyclopentenyl or cyclohexenyl; and is preferably cyclohexenyl; (C _2-6 )heterocyclene means having 2-6 a heterocyclic alkenyl group having one carbon atom (preferably 3-5 carbon atoms) and one hetero atom selected from N, O and/or S; preferably a (C _2-6 ) heterocycloalkenyl group is oxygen Cyclohexenyl and azacyclohexenyl.

In the above definition having a polyfunctional group, the point of attachment is on the last group.

In the definition of a substituent, when all of the alkyl hydrazines of the substituent are indicated as being optionally substituted, this also includes the alkyl portion of the alkoxy group.

A circle in the ring of formula (VIII) indicates that the ring is aromatic.

Depending on the ring formed, if nitrogen is present in X or Y, the nitrogen can carry hydrogen.

In a preferred embodiment, the invention relates to a compound according to formula (VIII), wherein B ₁ is C(R ₇ ); B ₂ is C(R ₈ ); B ₃ is C(R ₉ ), and B ₄ is C(R ₁₀ ).

In other embodiments, the BTK inhibitors include, but are not limited to, those described in the International Patent Application Publication No. WO 2013/010869, each of which is hereby incorporated by reference in its entirety.

In one embodiment, the BTK inhibitor is a compound of formula (IX): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal, or prodrug thereof, wherein: L _a is CH _2, O, NH or S; Ar is an aryl group or a substituted or non-substituted Substituted or unsubstituted heteroaryl; Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and Heteroaryl; Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O) _x , OS(=O) _x or NRS(=O) _x Wherein x is 1 or 2; R ⁷ and R ⁸ are each independently H; or R ⁷ and R ⁸ together form a bond; R ⁶ is H; and R is H or (C ₁ - ₆ )alkyl.

In a preferred embodiment, the BTK inhibitor is ibrutinib (also known as PCI-32765) or a pharmaceutically acceptable salt, ester, solvate, hydrate, eutectic or pharmaceutically acceptable salt thereof. medicine. In an exemplary embodiment, the BTK inhibitor is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d Pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof. In one embodiment, the BTK inhibitor is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] Pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof. In one embodiment, the BTK inhibitor is (S)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] Pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof. In a preferred embodiment, the BTK inhibitor has the structure of formula (X) or its mirror image isomer or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs :

In one embodiment, the BTK inhibitor is a compound of formula (XI): The acceptable or their pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal, or prodrug thereof, wherein: L _a is CH _2, O, NH or S; Ar is a substituted or unsubstituted aryl of a substituted or unsubstituted heteroaryl group; Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl And heteroaryl; Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O) _x , OS(=O) _x or NRS(=O ) _x, wherein x is 1 or 2; R ⁷ and R ⁸ are each H; or R ⁷ and R ⁸ together form a bond; ^{R. 6} is H; and R is H or (C ₁ - ₆₎ alkyl.

In one embodiment, the BTK inhibitor is a compound of formula (XII): The acceptable or their pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal, or prodrug thereof, wherein: L _a is CH _2, O, NH or S; Ar is a substituted or unsubstituted aryl of a substituted or unsubstituted heteroaryl group; Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl And heteroaryl; Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O) _x , OS(=O) _x or NRS(=O ) _x, wherein x is 1 or 2; R ⁷ and R ⁸ are each H; or R ⁷ and R ⁸ together form a bond; ^{R. 6} is H; and R is H or (C ₁ - ₆₎ alkyl.

In one embodiment, the BTK inhibitor is a compound of formula (XIII): The acceptable or their pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal, or prodrug thereof, wherein: L _a is CH _2, O, NH or S; Ar is a substituted or unsubstituted aryl of a substituted or unsubstituted heteroaryl group; Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl And heteroaryl; Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O) _x , OS(=O) _x or NRS(=O _x wherein x is 1 or 2; R ⁷ and R ⁸ are each H; or R ⁷ and R ⁸ together form a bond; R ⁶ is H; and R is H or (C ₁ - ₆ )alkyl.

In one embodiment, the BTK inhibitor is a compound disclosed in U.S. Patent No. 7,459,554, the disclosure of which is incorporated herein by reference. In one embodiment, the BTK inhibitor is a compound of formula (XIV): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, wherein: Q ¹ is aryl ¹ , heteroaryl ¹ , cycloalkyl, heterocyclyl, cycloalkenyl or a heterocycloalkenyl group, any of which is optionally substituted by 1 to 5 independent G ¹ substituents; R ¹ is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, An aralkyl group, a heteroarylalkyl group, a heterocyclic group or a heterobicycloalkyl group, any of which is optionally substituted by one or more independent G ¹¹ substituents; G ¹ and G ⁴¹ are each independently Halo, keto, -CF ₃ , -OCF ₃ , -OR ² , -NR ² R ³ (R ^3a ) _j1 , -C(O)R ² , -CO ₂ R ² , -CONR ² R ³ , - NO ₂ , -CN, -S(O) _j1 R ² , -SO ₂ NR ² R ³ , NR ² (C=O)R ³ , NR ² (C=O)OR ³ , NR ² (C=O) NR ² R ³ , NR ² S(O) _j1 R ³ , -(C=S)OR ² , -(C=O)SR ² , -NR ² (C=NR ³ )NR ^2a R ^3a , -NR ² (C=NR ³ )OR ^2a , -NR ² (C=NR ³ )SR ^3a , -O(C=O)OR ² , -O(C=O)NR ² R ³ , -O(C=O) SR ² , -S(C=O)OR ² , -S(C=O)NR ² R ³ , (C _0-10 )alkyl, (C _2-10 )alkenyl, (C _2-10 )alkyne (C _1-10 ) alkoxy (C _1-10 ) alkyl, (C _{1 -10} ) alkoxy (C _2-10 ) alkenyl, (C _1-10 ) alkoxy (C _2-10 ) alkynyl, (C _1-10 ) alkylthio (C _1-10 ) alkyl (C _1-10 )alkylthio (C _2-10 )alkenyl, (C _1-10 )alkylthio (C _2-10 )alkynyl, cyclo(C _3-8 )alkyl, ring (C _3-8 ) alkenyl, cyclo(C _3-8 )alkyl(C _1-10 )alkyl, cyclo(C _3-8 )alkenyl(C _1-10 )alkyl, ring (C _3-8 ) Alkyl (C _2-10 ) alkenyl, cyclo (C _3-8 ) alkenyl (C _2-10 ) alkenyl, cyclo (C _3-8 ) alkyl (C _2-10 ) alkynyl, ring (C _3-8 ) alkenyl (C _2-10 ) alkynyl, heterocyclyl-(C _0-10 )alkyl, heterocyclyl-(C _2-10 )alkenyl or heterocyclyl-(C _2-10 ) alkynyl, any of those groups optionally substituted by one or more independent one of the following substituents: halo, _{keto, -CF 3, -OCF 3, -OR} 222, -NR 222 R 333 (R ³³³ a) _j1a , -C(O)R ²²² , -CO ₂ R ²²² , -CONR ²²² R ³³³ , -NO ₂ , -CN, -S(O) _j1a R ²²² , -SO ₂ NR ²²² R ³³³ , NR ²²² (C=O)R ³³³ , NR ²²² (C=O)OR ³³³ , NR ²²² (C=O)NR ²²² R ³³³ , NR ²²² S(O) _j1a R ³³³ , -(C=S)OR ²²² , -(C=O)SR ²²² , -NR ²²² (C=NR ³³³ )NR ^222a R ^333a , -NR ²²² (C=NR ³³³ )OR ^222a , -NR ²²² (C=NR ³³³ )SR ^333a , -O(C=O)OR ²²² , -O(C=O)NR ²²² R ³³³ , -O(C=O)SR ²²² , -S(C=O)OR ²²² or -S(C=O) NR ²²² R ³³³ ; or -(X ¹ ) _n -(Y ¹ ) _m -R ⁴ ; or aryl-(C _0-10 )alkyl, aryl-(C _2-10 )alkenyl or aryl- (C _2-10 ) alkynyl, any of which is optionally substituted by one or more independent substituents: halo, -CF ₃ , -OCF ₃ , -OR ²²² , -NR ²²² R ³³³ (R ^333a ) _j2a , -C(O)R ²²² , -CO ₂ R ²²² , -CONR ²²² R ³³³ , -NO ₂ , -CN, -S(O) _j2a R ²²² , -SO ₂ NR ²²² R ³³³ , NR ²²² (C=O)R ³³³ , NR ²²² (C=O)OR ³³³ , NR ²²² (C=O)NR ²²² R ³³³ , NR ²²² S(O) _j2a R ³³³ , -(C=S) OR ²²² , -(C=O)SR ²²² , -NR ²²² (C=NR ³³³ )NR ^222a R ^333a , -NR ²²² (C=NR ³³³ )OR ^222a , -NR ²²² (C=NR ³³³ )SR ^333a , -O(C=O)OR ²²² , -O(C=O)NR ²²² R ³³³ , -O(C=O)SR ²²² , -S(C=O)OR ²²² or -S(C=O)NR ²²² R ³³³ ; or heteroaryl-(C _0-10 )alkyl, heteroaryl-(C _2-10 )alkenyl or heteroaryl-(C _2-10 )alkynyl, in such groups any one of optionally substituted independently by one or more of the following substituents: _{halo, -CF 3, -OCF 3, -OR} 222, -NR ²²² , R ³³³ (R ^333a ) _j3a , -C(O)R ²²² , -CO ₂ R ²²² , -CONR ²²² R ³³³ , -NO ₂ , -CN, -S(O) _j3a R ²²² , -SO ₂ NR ²²² R ³³³ , NR ²²² (C=O)R ³³³ , NR ²²² (C=O)OR ³³³ , NR ²²² (C=O)NR ²²² R ³³³ , NR ²²² S(O) _j3a R ³³³ , -(C= S) OR ²²² , -(C=O)SR ²²² , -NR ²²² (C=NR ³³³ )NR ²²² aR ³³³ a, -NR ²²² (C=NR ³³³ )OR ^222a , -NR ²²² (C=NR ³³³ ) SR ³³³ a, -O(C=O)OR ²²² , -O(C=O)NR ²²² R ³³³ , -O(C=O)SR ²²² , -S(C=O)OR ²²² , or -S( C=O)NR ²²² R ³³³ ; G ¹¹ is halo, keto, -CF ₃ , -OCF ₃ , -OR ²¹ , -NR ²¹ R ³¹ (R ^3a1 ) _j4 , -C(O)R ²¹ ,- CO ₂ R ²¹ , -CONR ²¹ R ³¹ , -NO ₂ , -CN, -S(O) _j4 R ²¹ , -SO ₂ NR ²¹ R ³² , NR ²¹ (C=O)R ³¹ , NR ²¹ (C= O) OR ³¹ , NR ²¹ (C=O) NR ²¹ R ³¹ , NR ²¹ S(O) _j4 R ³¹ , -(C=S)OR ²¹ , -(C=O)SR ²¹ , -NR ²¹ (C =NR ³¹ )NR ^2a1 R ^3a1 , -NR ²¹ (C=NR ³¹ )OR ^2a1 , -NR ²¹ (C=NR ³¹ )SR ^3a1 , -O(C=O)OR ²¹ , -O(C=O) NR ²¹ R ³¹ , -O(C=O)SR ²¹ , -S(C=O)OR ²¹ , -S(C=O)NR ²¹ R ³¹ , -P(O)OR ²¹ OR ³¹ , (C _{0 -10)} alkyl, (C _2-10) alkenyl, (C _2-10) alkynyl , (C _1-10) alkoxy (C _1-10) alkyl, (C _1-10) alkoxy (C _2-10) alkenyl, (C _1-10) alkoxy (C _{2- 10} ) alkynyl, (C _1-10 )alkylthio(C _1-10 )alkyl, (C _1-10 )alkylthio (C _2-10 )alkenyl, (C _1-10 )alkylthio (C _2-10 )alkynyl, cyclo(C _3-8 )alkyl, cyclo(C _3-8 )alkenyl, cyclo(C _3-8 )alkyl(C _1-10 )alkyl, ring (C _3-8 ) alkenyl (C _1-10 )alkyl, cyclo(C _3-8 )alkyl(C _2-10 )alkenyl, cyclo(C _3-8 )alkenyl(C _2-10 )alkenyl , (C _3-8 )alkyl (C _2-10 ) alkynyl, cyclo (C _3-8 )alkenyl (C _2-10 ) alkynyl, heterocyclyl-(C _0-10 )alkyl, Heterocyclyl-(C _2-10 )alkenyl or heterocyclyl-(C _2-10 )alkynyl, any of which may be optionally substituted with one or more of the following substituents: halogen Ketone group, keto group, -CF ₃ , -OCF ₃ , -OR ²²²¹ , -NR ²²²¹ R ³³³¹ (R ^333a1 ) _j4a , -C(O)R ²²²¹ , -CO ₂ R ²²²¹ , -CONR ²²²¹ R ³³³¹ , -NO ₂ , -CN, -S(O) _j4a R ²²²¹ , -SO ₂ NR ²²²¹ R ³³³¹ , NR ²²²¹ (C=O)R ³³³¹ , NR ²²²¹ (C=O)OR ³³³¹ , NR ²²²¹ (C=O)NR ²²²¹ R ³³³¹ , NR ²²²¹ S(O) _j4a R ³³³¹ , -(C=S)OR ²²²¹ , -(C=O)SR ²²²¹ , -NR ²²²¹ (C=NR ³³³¹ )NR ^222a1 R ^333a1 , -NR ²²²¹ (C=NR ³³³¹ )OR ^222a1 , -NR ²²²¹ (C=NR ³³³¹ )SR ^333a1 , -O(C=O)OR ²²²¹ , -O(C=O)NR ²²²¹ R ³³³¹ ,- O(C=O)SR ²²²¹ , -S(C=O)OR ²²²¹ , -P(O)OR ²²²¹ OR ³³³¹ or -S(C=O)NR ²²²¹ R ³³³¹ ; or aryl-(C _0-10 An alkyl, aryl-(C _2-10 )alkenyl or aryl-(C _2-10 )alkynyl group, any of which is optionally substituted by one or more of the following substituents independently : halo, -CF ₃ , -OCF ₃ , -OR ²²²¹ , -NR ²²²¹ R ³³³¹ (R ^333a1 ) _j5a , -C(O)R ²²²¹ , -CO ₂ R ²²²¹ , -CONR ²²²¹ R ³³³¹ , -NO ₂ , -CN, -S(O) _j5a R ²²²¹ , -SO ₂ NR ²²²¹ R ³³³¹ , NR ²²²¹ (C=O)R ³³³¹ , NR ²²²¹ (C=O)OR ³³³¹ , NR ²²²¹ (C=O)NR ²²²¹ R ³³³¹ , NR ²²²¹ S(O) _j5a R ³³³¹ , -(C=S)OR ²²²¹ , -(C=O)SR ²²²¹ , -NR ²²²¹ (C=NR ³³³¹ )NR ^222a1 R ^333a1 , -NR ²²²¹ (C =NR ³³³¹ )OR ^222a1 , -NR ²²²¹ (C=NR ³³³¹ )SR ^333a1 , -O(C=O)OR ²²²¹ , -O(C=O)NR ²²²¹ R ³³³¹ , -O(C=O)SR ²²²¹ , -S(C=O)OR ²²²¹ , -P(O)OR ²²²¹ R ³³³¹ or -S(C=O)NR ²²²¹ R ³³³¹ ; or heteroaryl-(C _0-10 )alkyl, heteroaryl -(C _2-10 )alkenyl or heteroaryl-(C _2-10 An alkynyl group, any of which is optionally substituted by one or more independent substituents: halo, -CF ₃ , -OC _F3 , -OR ²²²¹ , -NR ²²²¹ R ³³³¹ (R ^333a1 _J6a , -C(O)R ²²²¹ , -CO ₂ R ²²²¹ , -CONR ²²²¹ R ³³³¹ , -NO ₂ , -CN, -S(O) _j6a R ²²²¹ , -SO ₂ NR ²²²¹ R ³³³¹ , NR ²²²¹ ( C=O)R ³³³¹ , NR ²²²¹ (C=O)OR ³³³¹ , NR ²²²¹ (C=O)NR ²²²¹ R ³³³¹ , NR ²²²¹ S(O) _j6a R ³³³¹ , -(C=S)OR ²²²¹ ,-( C=O)SR ²²²¹ , -NR ²²²¹ (C=NR ³³³¹ )NR ^222a1 R ^333a1 , -NR ²²²¹ (C=NR ³³³¹ )OR ^222a1 , -NR ²²²¹ (C=NR ³³³¹ )SR ^333a1 , -O(C= O) OR ²²²¹ , -O(C=O)NR ²²²¹ R ³³³¹ , -O(C=O)SR ²²²¹ , -S(C=O)OR ²²²¹ , -P(O)OR ²²²¹ OR ³³³¹ or -S( C=O)NR ²²²¹ R ³³³¹ ; or G ¹¹ together with the carbon to which it is bonded form a double bond substituted with R ⁵ and G ¹¹¹ ; R ² , R ^2a , R ³ , R ^3a , R ²²² , R ²²² a, R ³³³ And R ^333a , R ²¹ , R ^2a1 , R ³¹ , R ^3a1 , R ²²²¹ , R ^222a1 , R ³³³¹ and R ^333a1 are each independently equal to (C _0-10 )alkyl, (C _2-10 )alkenyl, ( C _2-10 ) alkynyl, (C _1-10 ) alkoxy (C _1-10 ) alkyl, (C _1-10 ) alkoxy (C _2-10 ) Alkenyl, (C _1-10 )alkoxy(C _2-10 )alkynyl, (C _1-10 )alkylthio(C _1-10 )alkyl, (C _1-10 )alkylthio (C _2-10 ) alkenyl, (C _1-10 )alkylthio (C _2-10 )alkynyl, cyclo(C _3-8 )alkyl, cyclo(C _3-8 )alkenyl, ring (C _{3- 8} ) alkyl (C _1-10 ) alkyl, cyclo (C _3-8 ) alkenyl (C _1-10 ) alkyl, cyclo (C _3-8 ) alkyl ( _2-10 ) alkenyl, ring ( C _3-8 )alkenyl(C _2-10 )alkenyl, cyclo(C _3-8 )alkyl(C _2-10 )alkynyl,cyclo(C _3-8 )alkenyl(C _2-10 )alkyne Any of these groups, a heterocyclyl-(C _0-10 )alkyl, a heterocyclyl-(C _2-10 )alkenyl or a heterocyclyl-(C _2-10 )alkynyl group Optionally substituted with one or more G ¹¹¹ substituents; or aryl-(C _0-10 )alkyl, aryl-(C _2-10 )alkenyl or aryl-(C _2-10 )alkynyl, a heteroaryl-(C _0-10 )alkyl, heteroaryl-(C _2-10 )alkenyl or heteroaryl-(C _2-10 )alkynyl group, any of which is optionally Substituted by one or more G ¹¹¹ substituents; or in -NR ² R ³ (R ^3a ) _j1 or -NR ²²² R ³³³ (R ³³³ a) _j1a or -NR ²²² R ³³³ (R ³³³ a) _j2a or -NR ²²²¹ R ³³³¹ (R ^333a1 ) _j3a or -NR ²²²¹ R ³³³¹ (R ^333a1 ) _j4a or -NR ²²²¹ R ³³³¹ (R ^333a1 ) _j5a or -NR ²²²¹ R ³³³¹ (R ^333a1 ) _In the example of _j6a , R ² and R ³ , or R ²²² and R ³³³ 3 , or R ²²²¹ and R ³³³¹ together with the nitrogen atom to which they are bonded form a 3-10 membered saturated ring, an unsaturated ring, and a hetero atom. a ring-saturated or heterocyclic unsaturated ring wherein the ring is optionally substituted with one or more G ¹¹¹ substituents; X ¹ and Y ¹ are each independently -O-, -NR ⁷ -, -S(O) _j7 - , -CR ⁵ R ⁶ -, -N(C(O)OR ⁷ )-, -N(C(O)R ⁷ )-, -N(SO ₂ R ⁷ )-, -CH ₂ O-, -CH ₂ S-, -CH ₂ N(R ⁷ )-, -CH(NR ⁷ )-, -CH ₂ N(C(O)R ⁷ )-, -CH ₂ N(C(O)OR ⁷ )-, -CH ₂ N(SO ₂ R ⁷ )-, -CH(NHR ⁷ )-, -CH(NHC(O)R ⁷ )-, -CH(NHSO ₂ R ⁷ )-, -CH(NHC(O)OR ⁷ ) -, -CH(OC(O)R ⁷ )-, -CH(OC(O)NHR ⁷ )-, -CH=CH-, -C.ident.C-, -C(=NOR ⁷ )- , -C(O)-, -CH(OR ⁷ )-, -C(O)N(R ⁷ )-, -N(R ⁷ )C(O)-, -N(R ⁷ )S(O) -, -N(R ⁷ )S(O) ₂ --OC(O)N(R ⁷ )-, -N(R ⁷ )C(O)N(R ⁷ )-, -NR ⁷ C(O) O-, -S(O)N(R ⁷ )-, -S(O) ₂ N(R ⁷ )-, -N(C(O)R ⁷ )S(O)-, -N(C(O) R ⁷ )S(O) ₂ -, -N(R ⁷ )S(O)N(R ⁷ )-, -N(R ⁷ )S(O) ₂ N(R ⁷ )-, -C(O N(R ⁷ )C(O)-, -S(O)N(R ⁷ )C(O)-, -S(O) ₂ N(R ⁷ )C(O)-, -OS(O) N(R ⁷ )-, -OS(O) ₂ N(R ⁷ )-, -N(R ⁷ )S(O)O-, -N(R ⁷ )S(O) ₂ O-, -N(R ⁷ )S(O)C(O)-, -N( R ⁷ )S(O) ₂ C(O)-, -SON(C(O)R ⁷ )-, -SO ₂ N(C(O)R ⁷ )-, -N(R ⁷ )SON(R ⁷ )-, -N(R ⁷ )SO ₂ N(R ⁷ )-, -C(O)O-, -N(R ⁷ )P(OR ⁸ )O-, -N(R ⁷ )P(OR ⁸ )-, -N(R ⁷ )P(O)(OR ⁸ )O-, -N(R ⁷ )P(O)(OR ⁸ )-, -N(C(O)R ⁷ )P(OR ⁸ O-, -N(C(O)R ⁷ )P(OR ⁸ )-, -N(C(O)R ⁷ )P(O)(OR ⁸ )O-, -N(C(O)R ⁷ ) P(OR ⁸ )-, -CH(R ⁷ )S(O)-, -CH(R ⁷ )S(O) ₂ -, -CH(R ⁷ )N(C(O)OR ⁷ )- , -CH(R ⁷ )N(C(O)R ⁷ )-, -CH(R ⁷ )N(SO ₂ R ⁷ )-, -CH(R ⁷ )O-, -CH(R ⁷ )S- , -CH(R ⁷ )N(R ⁷ )-, -CH(R ⁷ )N(C(O)R ⁷ )-, -CH(R ⁷ )N(C(O)OR ⁷ )-, -CH (R ⁷ )N(SO ₂ R ⁷ )-, -CH(R ⁷ )C(=NOR ⁷ )-, -CH(R ⁷ )C(O)-, -CH(R ⁷ )CH(OR ⁷ ) -, -CH(R ⁷ )C(O)N(R ⁷ )-, -CH(R ⁷ )N(R ⁷ )C(O)-, -CH(R ⁷ )N(R ⁷ )S(O )-, -CH(R ⁷ )N(R ⁷ )S(O) ₂ -, -CH(R ⁷ )OC(O)N(R ⁷ )-, -CH(R ⁷ )N(R ⁷ )C (O)N(R ⁷ )-, -CH(R ⁷ )NR ⁷ C(O)O-, -CH(R ⁷ )S(O)N(R ⁷ )-, -CH(R ⁷ )S( O) ₂ N(R ⁷ )-, -CH(R ⁷ )N(C(O)R ⁷ )S(O)-, -CH(R ⁷ )N(C(O)R ⁷ )S(O) -, -CH(R ⁷ )N(R ⁷ )S(O)N(R ⁷ )-, -CH(R ⁷ )N(R ⁷ )S( O) ₂ N(R ⁷ )-, -CH(R ⁷ )C(O)N(R ⁷ )C(O)-, -CH(R ⁷ )S(O)N(R ⁷ )C(O) -, -CH(R ⁷ )S(O) ₂ N(R ⁷ )C(O)-, -CH(R ⁷ )OS(O)N(R ⁷ )-, -CH(R ⁷ )OS(O ₂ N(R ⁷ )-, -CH(R ⁷ )N(R ⁷ )S(O)O-, -CH(R ⁷ )N(R ⁷ )S(O) ₂ O-, -CH(R ⁷ ) N(R ⁷ )S(O)C(O)-, -CH(R ⁷ )N(R ⁷ )S(O) ₂ C(O)-, -CH(R ⁷ )SON(C(O) R ⁷ )-, -CH(R ⁷ )SO ₂ N(C(O)R ⁷ )-, -CH(R ⁷ )N(R ⁷ )SON(R ⁷ )-, -CH(R ⁷ )N (R ⁷ )SO ₂ N(R ⁷ )-, -CH(R ⁷ )C(O)O-, -CH(R ⁷ )N(R ⁷ )P(OR ⁸ )O-, -CH(R ⁷ N(R ⁷ )P(OR ⁸ )-, -CH(R ⁷ )N(R ⁷ )P(O)(OR ⁸ )O-, -CH(R ⁷ )N(R ⁷ )P(O) (OR ⁸ )-, -CH(R ⁷ )N(C(O)R ⁷ )P(OR ⁸ )O-, -CH(R ⁷ )N(C(O)R ⁷ )P(OR ⁸ )- , -CH(R ⁷ )N(C(O)R ⁷ )P(O)(OR ⁸ )O- or -CH(R ⁷ )N(C(O)R ⁷ )P(OR ⁸ )-; X ¹ and Y ¹ are each independently represented by one of the following structural formulas: R ¹⁰ together with phosphinamide or phosphonamide is a 5, 6 or 7 membered aryl, heteroaryl or heterocyclyl ring system; R ⁵ , R ⁶ and G ¹¹¹ are each independently (C ₀ - ₁₀ )alkyl, (C ₂ - ₁₀ ) alkenyl, (C ₂ - ₁₀ ) alkynyl, (C ₁ - ₁₀ ) alkoxy (C ₁ - ₁₀ ) alkyl, (C ₁ - ₁₀ ) alkane Oxy (C ₂ - ₁₀ ) alkenyl, (C ₁ - ₁₀ ) alkoxy (C ₂ - ₁₀ ) alkynyl, (C ₁ - ₁₀ ) alkylthio (C ₁ - ₁₀ ) alkyl, (C ₁ - ₁₀ ) alkylthio (C ₂ - ₁₀ ) alkenyl, (C ₁ - ₁₀ ) alkylthio (C ₂ - ₁₀ ) alkynyl, cyclo (C ₃ - ₈ ) alkyl, ring (C ₃ - ₈ ) Alkenyl, cyclo(C ₃ - ₈ )alkyl (C ₁ - ₁₀ ) alkyl, cyclo (C ₃ - ₈ ) alkenyl (C ₁ - ₁₀ ) alkyl, cyclo (C ₃ - ₈ ) alkyl (C ₂ - ₁₀ ) alkenyl, cyclo(C ₃ - ₈ ) alkenyl (C ₂ - ₁₀ ) alkenyl, cyclo (C ₃ - ₈ ) alkyl (C ₂ - ₁₀ ) alkynyl, ring (C ₃ - ₈ ) Alkenyl (C ₂ - ₁₀ ) alkynyl, heterocyclyl-(C ₀ - ₁₀ )alkyl, heterocyclyl-(C ₂ - ₁₀ ) alkenyl or heterocyclyl-(C ₂ - ₁₀ ) alkynyl, any one of those groups optionally substituted by one or more substituents independently a group of the following substituents: _{halo, -CF 3, -OCF 3, -OR} 77, -NR 77 R 87, -C (O) R ⁷⁷ , -CO ₂ R ⁷⁷ , -CONR ⁷⁷ R ⁸⁷ , -NO ₂ , -CN, -S(O) _j5a R ⁷⁷ , -SO ₂ NR ⁷⁷ R ⁸⁷ , NR ⁷⁷ (C=O)R ⁸⁷ , NR ⁷⁷ (C=O)OR ⁸⁷ , NR ⁷⁷ (C= O) NR ⁷⁸ R ⁸⁷ , NR ⁷⁷ S(O) _j5a R ⁸⁷ , -(C=S)OR ⁷⁷ , -(C=O)SR ⁷⁷ , -NR ⁷⁷ (C=NR ⁸⁷ )NR ⁷⁸ R ⁸⁸ ,- NR ⁷⁷ (C=NR ⁸⁷ )OR ⁷⁸ , -NR ⁷⁷ (C=NR ⁸⁷ )SR ⁷⁸ , -O(C=O)OR ⁷⁷ , -O(C=O)NR ⁷⁷ R ⁸⁷ , -O(C= O) SR ⁷⁷ , -S(C=O)OR ⁷⁷ , -P(O)OR ⁷⁷ OR ⁸⁷ or -S(C=O)NR ⁷⁷ R ⁸⁷ ; or aryl-(C ₀ - ₁₀ )alkyl, An aryl-(C _{2 -10} )alkenyl or aryl-(C _{2 -10} ) alkynyl group, any of which may be optionally substituted with one or more of the following substituents: halo, -CF ₃ , -OCF ₃ , -OR ⁷⁷ , -NR ⁷⁷ R ⁸⁷ , -C(O)R ⁷⁷ , -CO ₂ R ⁷⁷ , -CONR ⁷⁷ R ⁸⁷ , -NO ₂ , -CN, -S(O) _J5a R ⁷⁷ , -SO ₂ NR ⁷⁷ R ⁸⁷ , NR ⁷⁷ (C=O)R ⁸⁷ , NR ⁷⁷ (C=O)OR ⁸⁷ , NR ⁷⁷ (C=O)NR ⁷⁸ R ⁸⁷ , NR ⁷⁷ S(O) _J5a R ⁸⁷ , -(C=S)OR ⁷⁷ , -(C=O)SR ⁷⁷ , -NR ⁷⁷ (C=NR ⁸⁷ )NR ⁷⁸ R ⁸⁸ , -NR ⁷⁷ (C=NR ⁸⁷ )OR ⁷⁸ , -NR ⁷⁷ (C=NR ⁸⁷ )SR ⁷⁸ , -O(C=O)OR ⁷⁷ , -O(C=O)NR ⁷⁷ R ⁸⁷ , -O(C=O)SR ⁷⁷ , -S(C=O)OR ^{77, -P (O) oR 77} R 87 or ^{-S (C = O) NR 77} R 87; or heteroaryl Group - (C ₀ - ₁₀₎ alkyl, heteroaryl - (C ₂ - ₁₀₎ alkenyl or heteroaryl -, any one of those groups - (C _{2 10)} alkynyl group optionally substituted by one one Or a plurality of independent substituents substituted: halo, -CF ₃ , -OCF ₃ , -OR ⁷⁷ , -NR ⁷⁷ R ⁸⁷ , -C(O)R ⁷⁷ , -CO ₂ R ⁷⁷ , -CONR ⁷⁷ R ⁸⁷ , -NO ₂ , -CN, -S(O) _j5a R ⁷⁷ , -SO ₂ NR ⁷⁷ R ⁸⁷ , NR ⁷⁷ (C=O)R ⁸⁷ , NR ⁷⁷ (C=O)OR ⁸⁷ , NR ⁷⁷ (C= O) NR ⁷⁸ R ⁸⁷ , NR ⁷⁷ S(O) _j5a R ⁸⁷ , -(C=S)OR ⁷⁷ , -(C=O)SR ⁷⁷ , -NR ⁷⁷ (C=NR ⁸⁷ )NR ⁷⁸ R ⁸⁸ ,- NR ⁷⁷ (C=NR ⁸⁷ )OR ⁷⁸ , -NR ⁷⁷ (C=NR ⁸⁷ )SR ⁷⁸ , -O(C=O)OR ⁷⁷ , -O(C=O)NR ⁷⁷ R ⁸⁷ , -O(C= O) SR ⁷⁷ , -S(C=O)OR ⁷⁷ , -P(O)OR ⁷⁷ OR ⁸⁷ or -S(C=O)NR ⁷⁷ R ⁸⁷ ; or each of the carbons to which R ⁵ and R ^{6 are} attached The atoms together form a 3-10 membered saturated or unsaturated ring wherein the ring is optionally substituted with R ⁶⁹ ; or R ⁵ and R ⁶ together with the respective carbon atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring. ring, wherein the ring is optionally substituted with R ^69; R ⁷ and R ⁸ are each independently H, acyl, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl or cycloalkyl, which groups Any one of the optionally substituted by one or more G ¹¹¹ substituents; R ⁴ is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl or a heterocycloalkenyl group, any of which is optionally substituted with one or more G ⁴¹ substituents; R ⁶⁹ is equal to halo, -OR ⁷⁸ , -SH, -NR ⁷⁸ R ⁸⁸ , -CO ₂ R ⁷⁸ , -CONR ⁷⁸ R ⁸⁸ , -NO ₂ , -CN, -S(O) _j8 R ⁷⁸ , -SO ₂ NR ⁷⁸ R ⁸⁸ , (C ₀ - ₁₀ ) alkyl, (C ₂ - ₁₀ ) alkenyl, (C ₂ - ₁₀ ) alkynyl, (C ₁ - ₁₀ ) alkoxy (C ₁ - ₁₀ ) alkyl, (C ₁ - ₁₀ ) alkoxy (C ₂ - ₁₀ ) alkenyl, (C ₁ - ₁₀ Alkoxy (C ₂ - ₁₀ ) alkynyl, (C ₁ - ₁₀ ) alkylthio (C ₁ - ₁₀ ) alkyl, (C ₁ - ₁₀ ) alkylthio (C ₂ - ₁₀ ) alkenyl, C ₁ - ₁₀ ) alkylthio (C ₂ - ₁₀ ) alkynyl, cyclo (C ₃ - ₈ ) alkyl, cyclo (C ₃ - ₈ ) alkenyl, cyclo (C ₃ - ₈ ) alkyl (C ₁ - ₁₀ ) alkyl, cyclo(C ₃ - ₈ ) alkenyl (C ₁ - ₁₀ ) alkyl, cyclo (C ₃ - ₈ ) alkyl (C ₂ - ₁₀ ) alkenyl, cyclo (C ₃ - ₈ ) alkenyl (C ₂ - ₁₀ ) alkenyl, cyclo(C ₃ - ₈ )alkyl (C ₂ - ₁₀ ) alkynyl, cyclo (C ₃ - ₈ ) alkenyl (C ₂ - ₁₀ ) alkynyl, heterocyclyl-( C ₀ - ₁₀ )alkyl, heterocyclic-(C ₂ - ₁₀ ) an alkenyl or heterocyclyl-(C ₂ - ₁₀ ) alkynyl group, any of which is optionally substituted by one or more independent substituents: halo, cyano, nitro, -OR ⁷⁷⁸ , -SO ₂ NR ⁷⁷⁸ R ⁸⁸⁸ , or -NR ⁷⁷⁸ R ⁸⁸⁸ ; or aryl-(C ₀ - ₁₀ )alkyl, aryl-(C ₂ - ₁₀ )alkenyl or aryl-(C ₂ - ₁₀ ) alkynyl, any of which is optionally substituted by one or more of the following substituents: halo, cyano, nitro, -OR ⁷⁷⁸ , (C _1-10 )alkyl (C _2-10 )alkenyl, (C _2-10 )alkynyl, halo(C _1-10 )alkyl, halo(C _2-10 )alkenyl, halo(C _2-10 )alkyne a group, -COOH, (C _1-4 ) alkoxycarbonyl, -CONR ⁷⁷⁸ R ⁸⁸⁸ , -SO ₂ NR ⁷⁷⁸ R ⁸⁸⁸ or -NR ⁷⁷⁸ R ⁸⁸⁸ ; or a heteroaryl-(C _0-10 )alkyl group, Heteroaryl-(C _2-10 )alkenyl or heteroaryl-(C _2-10 )alkynyl, any of which may be optionally substituted by one or more of the following substituents: halogen , cyano, nitro, -OR ⁷⁷⁸ , (C _1-10 )alkyl, (C _2-10 )alkenyl, (C _2-10 )alkynyl, halo(C _1-10 )alkyl, halo (C _2-10) alkenyl group, halo (C _2-10) alkynyl group, -COOH, (C _1-4) alkoxycarbonyl _{^{-CONR 778 R 888, -SO 2 NR}} 778 R 888 or -NR ⁷⁷⁸ R ^888; or mono (C _1-6 alkyl) amino (C _1-6) alkyl, di ((C _1-6) alkoxy Amino (C _1-6 )alkyl, mono(aryl)amino(C _1-6 )alkyl, bis(aryl)amino(C _1-6 )alkyl or -N((C _1-6 )alkyl)-(C _1-6 )alkyl-aryl, any of which may be optionally substituted by one or more of the following substituents: halo, cyano, nitrate , -OR ⁷⁷⁸ , (C _1-10 )alkyl, (C _2-10 )alkenyl, (C _2-10 )alkynyl, halo(C _1-10 )alkyl, halo (C _{2- 10} ) alkenyl, halo (C _2-10 ) alkynyl, -COOH, (C _1-4 ) alkoxycarbonyl, -CONR ⁷⁷⁸ R ⁸⁸⁸ , -SO ₂ NR ⁷⁷⁸ R ⁸⁸⁸ or -NR ⁷⁷⁸ R ⁸⁸⁸ ; Or in the case of -NR ⁷⁸ R ⁸⁸ , R ⁷⁸ and R ⁸⁸ together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring or heterocyclic unsaturated ring, wherein the ring Optionally substituted with one or more of the following substituents independently: halo, cyano, hydroxy, nitro, (C _1-10 )alkoxy, -SO ₂ NR ⁷⁷⁸ R ⁸⁸⁸ or -NR ⁷⁷⁸ R ⁸⁸⁸ ;R ⁷⁷ , R ⁷⁸ , R ⁸⁷ , R ⁸⁸ , R ⁷⁷⁸ and R ⁸⁸⁸ are each independently (C ₀ - ₁₀ )alkyl, (C ₂ - ₁₀ Alkenyl, (C ₂ - ₁₀ ) alkynyl, (C ₁ - ₁₀ ) alkoxy (C ₁ - ₁₀ ) alkyl, (C ₁ - ₁₀ ) alkoxy C ₂ - ₁₀ ) alkenyl, (C ₁ - ₁₀ ) alkoxy (C ₂ - ₁₀ ) alkynyl, (C ₁ - ₁₀ ) alkylthio (C ₁ - ₁₀ ) alkyl, (C ₁ - ₁₀ ) alkylthio (C ₂ - ₁₀ ) alkene , (C ₁ - ₁₀ )alkylthio (C ₂ - ₁₀ ) alkynyl, cyclo (C ₃ - ₈ ) alkyl, cyclo (C ₃ - ₈ ) alkenyl, cyclo (C ₃ - ₈ ) alkyl ( C ₁ - ₁₀ )alkyl, cyclo(C ₃ - ₈ )alkenyl (C ₁ - ₁₀ )alkyl, cyclo(C ₃ - ₈ )alkyl(C ₂ - ₁₀ )alkenyl, ring (C ₃ - ₈ Alkenyl (C ₂ - ₁₀ ) alkenyl, cyclo (C ₃ - ₈ ) alkyl (C ₂ - ₁₀ ) alkynyl, cyclo (C ₃ - ₈ ) alkenyl (C ₂ - ₁₀ ) alkynyl, heterocyclic -(C ₀ - ₁₀ )alkyl, heterocyclyl-(C ₂ - ₁₀ )alkenyl, heterocyclyl-(C ₂ - ₁₀ )alkynyl, (C ₁ - ₁₀ )alkylcarbonyl, (C ₂ - ₁₀ ) alkenylcarbonyl, (C ₂ - ₁₀ ) alkynylcarbonyl, (C ₁ - ₁₀ ) alkoxycarbonyl, (C ₁ - ₁₀ ) alkoxycarbonyl (C ₁ - ₁₀ ) alkyl, mono (C ₁ - ₆ ) alkylaminocarbonyl, di(C ₁ - ₆ )alkylaminocarbonyl, mono(aryl)aminocarbonyl, bis(aryl)aminocarbonyl or (C ₁ - ₁₀ )alkyl ( An aryl)aminocarbonyl group, any of which may optionally pass one or more Substituted independently of the following substituents: halo, cyano, hydroxy, nitro, (C _1-10 ) alkoxy, -SO ₂ N((C _0-4 )alkyl) ((C _0-4 ) Alkyl) or -N((C _0-4 )alkyl)((C _0-4 )alkyl); or aryl-(C _0-10 )alkyl, aryl-(C _2-10 ) ene Or an aryl-(C _2-10 )alkynyl group, any of which may be optionally substituted with one or more independent substituents: halo, cyano, nitro, -O(( C _0-4 )alkyl), (C _1-10 )alkyl, (C _2-10 )alkenyl, (C _2-10 )alkynyl, halo(C _1-10 )alkyl, halo ( C _2-10 ) alkenyl, halo (C _2-10 ) alkynyl, -COOH, (C _1-4 ) alkoxycarbonyl, -CON((C _0-4 )alkyl) ((C _{0- 10} ) alkyl), -SO ₂ N((C _0-4 )alkyl)((C _0-4 )alkyl) or -N((C _0-4 )alkyl)((C _0-4 ) Alkyl); or heteroaryl-(C _0-10 )alkyl, heteroaryl-(C _2-10 )alkenyl or heteroaryl-(C _2-10 )alkynyl, in such groups Either optionally substituted with one or more of the following substituents: halo, cyano, nitro, -O((C _0-4 )alkyl), (C _1-10 )alkyl, (C _2-10 ) alkenyl, (C _2-10 )alkynyl, halo(C _1-10 )alkyl, halo(C _2-10 )alkenyl, halo(C _2-10 )alkyne Base, -COOH, (C _1-4 ) alkoxycarbonyl, -CON((C _0-4 )alkyl)((C _0-4 )alkyl), -SO ₂ N((C _0-4 ) Alkyl)((C _0-4 )alkyl) or -N((C _0-4 )alkyl)((C _0-4 )alkyl); or mono((C _1-6 )alkyl)amine (C _1-6 )alkyl, bis((C _1-6 )alkyl)amino(C _1-6 )alkyl, mono(aryl)amino(C _1-6 )alkyl, di Aryl)amino(C _1-6 )alkyl or -N((C _1-6 )alkyl)-(C _1-6 )alkyl-aryl, any of these groups optionally Substituted by one or more of the following substituents: halo, cyano, nitro, -O((C _0-4 )alkyl), (C _1-10 )alkyl, (C _2-10 ) ene , (C _2-10 ) alkynyl, halo (C _1-10 ) alkyl, halo (C _2-10 ) alkenyl, halo (C _2-10 ) alkynyl, -COOH, (C _{1 -4} ) alkoxycarbonyl, -CON((C _0-4 )alkyl)((C _0-4 )alkyl), -SO ₂ N((C _0-4 )alkyl) ((C _{0- 4} ) alkyl) or -N((C _0-4 )alkyl)((C _0-4 )alkyl); and n, m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, J7 and j8 are each independently equal to 0, 1, or 2.

In one embodiment, the BTK inhibitor is selected from U.S. Patent Nos. 8,450,335 and 8,609,679, and U.S. Patent Application Publication Nos. 2010/0029610 A1, 2012/0077832 A1, 2013/0065879 A1, 2013/0072469 A1 and 2013/ Compounds of the structures disclosed in U.S. Patent No. 0, 165, the disclosure of which is incorporated herein by reference. In one embodiment, the BTK inhibitor is a compound of formula (XV) or (XVI):

Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, wherein: Ring A is a randomly substituted group selected from the group consisting of phenyl, 3-7 member saturated or Partially unsaturated carbon cyclic ring, 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, 5-6 membered monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur a heteroaryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, having from 1 to 5 independently selected from nitrogen, oxygen or Optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring of sulfur heteroatoms, or 8-10 membered bicyclic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur a heteroaryl ring; ring B is a randomly substituted group selected from the group consisting of phenyl, 3-7 membered saturated or partially unsaturated carbon ring, 8-10 membered bicyclic saturated, partially unsaturated Or an aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, having 1-3 independently selected from nitrogen, oxygen or sulfur 4-7 members of heteroatoms are saturated or partially unsaturated A heterocyclic ring, optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or having from 1 to 5 independent An 8-10 membered bicyclic heteroaryl ring selected from nitrogen, oxygen or sulfur heteroatoms; R ¹ is a warhead group; R ^y is hydrogen, halogen, -CN, -CF ₃ , C _1-4 aliphatic, C _1-4 aliphatic halo, -OR, -C (O) R, or -C (O) N (R) 2; each R is independently hydrogen or a group selected from the random Substituted group: C _1-6 aliphatic, phenyl, 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or having from 1 to 4 5-6 membered monocyclic heteroaryl rings independently selected from heteroatoms of nitrogen, oxygen or sulfur; W ¹ and W ² are each independently a covalent bond or a divalent C _1-3 alkyl chain, wherein W ¹ or a methylene unit of W ² optionally passes through -NR ² -, -N(R ² )C(O)-, -C(O)N(R ² )-, -N(R ² )SO ₂ -, -SO ₂ N(R ² )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- or -SO ₂ - Alternatively; R ² is hydrogen, optionally substituted with a substituent on the C _1-6 aliphatic or -C (O) R, or R ² and ring a with their intervening atoms to the group Together form a 4-6 membered saturated, partially unsaturated or aromatic fused ring, or R ² and R ^y with their intervening atoms to form together the optionally substituted 4-7 membered partially unsaturated or aromatic fused ring m and p are independently 0-4; and R ^x and R ^{y are} independently selected from -R, halogen, -OR, -O(CH ₂ ) _q OR, -CN, -NO ₂ , -SO ₂ R, - SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)NR ₂ ,- NRSO ₂ R or -N(R) ₂ , wherein q is 1-4; or: when R ^x and R ¹ coexist on ring B, they are formed together with their inserted atoms to have 0-3 independently selected a 5-7 membered saturated, partially unsaturated or aryl ring of a heteroatom of nitrogen, oxygen or sulfur wherein the ring is substituted with a warhead group and 0-3 groups independently selected from the group consisting of keto, halogen , -CN, or C _1-6 aliphatic; or when R ^v and R ¹ are co-exist on the ring a, is formed having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur together with their intervening atoms to a 5-7 membered saturated, partially unsaturated or aryl ring of an atom wherein the ring is substituted with a warhead group and 0-3 groups independently selected from the group consisting of keto, halo, -CN or _C1-6 Aliphatic.

In one embodiment, the BTK inhibitor is a compound of formula (XV) or formula (XVI) wherein ring A is selected from the group consisting of phenyl, 3 to 7 membered saturated or partially unsaturated carbon ring, 8 to 10 members. Bicyclic saturated, partially unsaturated or aryl ring, 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, having 1 to 3 independently Optionally substituted 4 to 7 membered saturated or partially unsaturated heterocyclic ring of a hetero atom selected from nitrogen, oxygen or sulfur, optionally having from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur Substituted 7 to 10 membered bicyclic saturated or partially unsaturated heterocyclic ring, or 8 to 10 membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; B is selected from the group consisting of phenyl, 3 to 7 membered saturated or partially unsaturated carbon ring, 8 to 10 membered bicyclic saturated, partially unsaturated or aryl ring, having 1 to 4 independently selected from nitrogen and oxygen. Or a randomly substituted 4 to 7 membered saturated or partially unsaturated heteroatom of a 5 to 6 membered monocyclic heteroaryl ring of a sulfur hetero atom, having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Annular ring with 1 Optionally substituted 7 to 10 membered bicyclic saturated or partially unsaturated heterocyclic ring independently selected from nitrogen, oxygen or sulfur heteroatoms, or having 1 to 5 independently selected from nitrogen, oxygen or 8 to 10 membered bicyclic heteroaryl ring of a hetero atom of sulfur; R ¹ is -LY, wherein: L is a covalent bond or a divalent C _1-8 saturated or unsaturated, linear or branched hydrocarbon group, wherein 1, 2 or 3 methylene units of L are optionally and independently ring-extended propyl, -NR-, -N(R)C(O)-, -C(O)N(R)-,- N(R)SO ₂ -, -SO ₂ N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO- , -SO ₂ -, -C(=S)-, -C(=NR)-, -N=N- or -C(=N ₂ )-substitution; Y is hydrogen, optionally ketone, halogen or CN substituted C _1-6 aliphatic, or a 3 to 10 membered monocyclic or bicyclic saturated, partially unsaturated or aryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and Wherein the ring is substituted with 1 to 4 groups independently selected from the group consisting of -QZ, keto, NO ₂ , halogen, CN or C _1-6 aliphatic, wherein: Q is a covalent bond or a divalent C _{1 -6} saturated or unsaturated, straight or branched chain hydrocarbon, wherein Q 1 or 2 methylene units optionally and independently By -NR -, - S -, - O -, - C (O) -, - SO- or -SO ₂ - Alternative; and Z is hydrogen or optionally substituted with keto, halogen, CN or C _1-6 of Aliphatic; R ^y is hydrogen, halogen, -CN, -CF ₃ , C _1-4 aliphatic, C _1-4 haloaliphatic, -OR, -C(O)R or -C(O)N ( R) ₂ ; each R group is independently hydrogen or an optionally substituted group selected from the group consisting of C _1-6 aliphatic, phenyl, having 1 to 2 independently selected from nitrogen, oxygen or sulfur. Optionally, a 4 to 7 membered heterocyclic ring of a heteroatom, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; W ¹ And W ² are each independently a covalent bond or a divalent C _1-3 alkyl chain, wherein one methylene unit of W ¹ or W ² is optionally subjected to -NR ² -, -N(R ² )C(O )-, -C(O)N(R ² )-, -N(R ² )SO ₂ -, -SO ₂ N(R ² )-, -O-, -C(O)-, -OC(O )-, -C(O)O-, -S-, -SO- or -SO ₂ - is substituted; R ² is hydrogen, optionally substituted C _1-6 aliphatic or -C(O)R, or The substituents on R ² and ring A together with their intervening atoms form a 4 to 6 membered partially unsaturated or aromatic fused ring; or R ² and R ^y together with their intervening atoms form 4 to 6 members saturation Partially unsaturated, or aromatic fused ring; m and p are independently 0-4; and R ^x represent and R ^v are independently selected -R, _{halo, -OR, -O (CH 2)} q OR, -CN, -NO ₂ , -SO ₂ R, -SO ₂ N(R) ₂ , -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R , -NRC(O)NR ₂ , -NRSO ₂ R or -N(R) ₂ , wherein R is independently selected from the group consisting of hydrogen, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, An aryl group, a heteroaryl group and a heterocyclic group; or: when R ^x and R ^{1 are} present on the ring B, together with their intervening atoms form 0 to 3 independently selected from nitrogen, oxygen or sulfur. a 5 to 7 membered saturated, partially unsaturated or aryl ring of a hetero atom wherein the ring is substituted with a warhead group and from 0 to 3 groups independently selected from the group consisting of keto, halo, -CN or C _{1- 6} aliphatic; or when R ^v and R ¹ coexist on ring A, together with their intervening atoms form a 5 to 7 member saturation with 0 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. a partially unsaturated or aryl ring wherein the ring is substituted with a warhead group and from 0 to 3 groups independently selected from the group consisting of keto, halogen, -CN or C _1-6 aliphatic.

As broadly defined above, Ring A is selected from the group consisting of phenyl, 3 to 7 membered saturated or partially unsaturated carbon ring, 8 to 10 membered bicyclic saturated, partially unsaturated or aryl ring, having 1 to 4 independently. 5 to 6 membered monocyclic heteroaryl rings of a hetero atom selected from nitrogen, oxygen or sulfur, 4 to 7 members having 1 to 3 hetero atoms independently selected from nitrogen, oxygen or sulfur, saturated or partially unsaturated a heterocyclic ring, optionally substituted 7 to 10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or having 1 to 5 independent An 8- to 10-membered bicyclic heteroaryl ring selected from heteroatoms of nitrogen, oxygen or sulfur.

In a preferred embodiment, Ring A is an optionally substituted phenyl group. In some embodiments, Ring A is an optionally substituted naphthyl ring, or an optionally substituted 8 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ring. In certain other embodiments, Ring A is a randomly substituted 3 to 7 membered carbon ring. In other In an embodiment, Ring A is a randomly substituted 4 to 7 membered heterocyclic ring having from 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In a preferred embodiment, Ring B is an optionally substituted phenyl group.

In certain embodiments, Ring A in Formula (XV) or Formula (XVI) is substituted, as defined herein. In some embodiments, Ring A is substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, R ^o or —(CH ₂ ) _0-4 OR ^o or —O(CH ₂ ) _{0- 4} R ^o , wherein each R ^{o is} independently selected from the group consisting of cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. A example of the ring substituents include Br, I, Cl, methyl, -CF _3, -C≡CH, -OCH ₂ phenyl, -OCH ₂ (fluorophenyl) pyridyl group or -OCH _2.

In a preferred embodiment, the BTK inhibitor is CC-292 (also known as AVL-292) or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, preferably It is its hydrochloride or besylate. In a preferred embodiment, the BTK inhibitor is a compound of formula (XVII): It is N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)propenylamine Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, or in its preferred embodiment, its hydrochloride or besylate salt. The preparation of this compound is described in Example 20 of U.S. Patent Application Publication No. 2010/0029610 A1, the disclosure of which is incorporated herein by reference. The preparation of a besylate salt of this compound (i.e., a benzenesulfonic acid salt) is described in U.S. Patent Application Publication No. 2012/0077832 A1, the disclosure of which is incorporated herein by reference. In one embodiment, the BTK inhibitor is a compound selected from the structures disclosed in U.S. Patent Application Publication No. 2010/0029610 A1, the disclosure of which is incorporated herein by reference.

In a preferred embodiment, the BTK inhibitor is N-(3-((5-fluoro-2-(2-methoxy)ethoxy)phenyl)pyrimidine-4- Amino)phenyl)propenylamine or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, or more preferably its hydrochloride or benzenesulfonate. The preparation of this compound is described in U.S. Patent Application Publication Nos. 2010/0029610 A1 and 2012/0077832 A1 which are incorporated herein by reference. The preparation of this compound is described in Example 20 of U.S. Patent Application Publication No. 2010/0029610 A1, the disclosure of which is incorporated herein by reference. The preparation of the besylate salt of this compound is described in U.S. Patent Application Publication No. 2012/0077832 A1, the disclosure of which is incorporated herein by reference.

In one embodiment, the BTK inhibitor is a compound of formula (XVIII): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, wherein: L represents (1)-O-, (2)-S-, (3)-SO-, ( 4) -SO ₂ -(5)-NH-, (6)-C(O)-, (7)-CH ₂ O-, (8)-O-CH ₂ -, (9)-CH ₂ - or (10)-CH(OH)-; R ¹ represents (1) a halogen atom, (2) C _1-4 alkyl, (3) C _1-4 alkoxy, (4) C _1-4 haloalkyl Or (5) C _1-4 haloalkoxy; ring 1 represents a 4 to 7 membered ring group which may be substituted with from 1 to 5 substituents each independently selected from the group consisting of: (1) a halogen atom, (2) C _1-4 alkyl, (3) C _1-4 alkoxy, (4) nitrile, (5) C _1-4 haloalkyl, and (6) C _1-4 halo An alkoxy group, wherein when two or more substituents are present on the ring 1, the substituents may form a 4 to 7 membered ring group together with the atoms of the ring 1 bonded to the substituents; ring 2 represents 4 to 7 members a saturated heterocyclic ring which may be substituted with from 1 to 3 -KR ² ; K represents a (1) bond, (2) C _1-4 alkylene, (3)-C(O)-, (4)-C (O)-CH ₂ -, (5)-CH ₂ -C(O)-, (6)-C(O)O- or (7)-SO ₂ - (wherein the bond on the left is bonded to ring 2); R ² represents (1) C _1-4 alkyl, (2) C _2-4 alkenyl group, or (3) C _2-4 alkynyl group, each such group May be from 1 to 5 substituents each independently selected from the group consisting of the following ^{substituents: (1) NR 3 R 4} , (2) a halogen ^{atom, (3) CONR 5 R 6} , (4) CO 2 R ⁷ and (5) OR ⁸ ; R ³ and R ⁴ each independently represent (1) a hydrogen atom or (2) C _1-4 alkyl group which may be substituted by OR ⁹ or CONR ¹⁰ R ¹¹ ; R ³ and R ⁴ may form, together with the nitrogen atom to which they are bonded, a 4 to 7 membered nitrogen-containing saturated heterocyclic ring which may be substituted with a keto group or a hydroxyl group; and R ⁵ and R ⁶ each independently represent (1) a hydrogen atom, (2) C _{1 -4} alkyl or (3) phenyl; R ⁷ represents (1) a hydrogen atom or (2) C _1-4 alkyl; R ⁸ represents (1) a hydrogen atom, (2) a C _1-4 alkyl group, ( 3) phenyl or (4) benzotriazolyl; R ⁹ represents (1) a hydrogen atom or (2) C _1-4 alkyl; R ¹⁰ and R ¹¹ each independently represent a (1) hydrogen atom or (2) C _1-4 alkyl; n represents an integer from 0 to 4; m represents an integer from 0 to 2; and when n is 2 or more, then R ¹ may be the same or different from each other.

In one embodiment, the BTK inhibitor is a compound of formula (XIX): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, eutectic or prodrug thereof, wherein: R ¹ represents (1) a halogen atom, (2) a C _1-4 alkyl group, and (3) C _{1 -4} alkoxy, (4) C _1-4 haloalkyl or (5) C _1-4 haloalkoxy; ring ₁ represents a benzene, cyclohexane or pyrimidine ring, each of which may be 1 to 5 are each independently substituted with a substituent selected from the group consisting of: (1) a halogen atom, (2) a C _1-4 alkyl group, a _{CDC 1-4} alkoxy group, (4) Nitrile, (5) CF ₃ ; ring 2 represents a 4- to 7-membered nitrogen-containing saturated heterocyclic ring which may be substituted with from 1 to 3 -KR ² ; wherein K represents a (1) bond, (2) C _1-4 alkane Base, (3)-C(O)-, (4)-C(O)-CH ₂ -, (5)-CH ₂ -C(O)-, (6)-C(O)O- or ( 7) -SO ₂ - (wherein the bond on the left is bonded to ring ² ); R ² represents (1) C _1-4 alkyl, (2) C _2-4 alkenyl or (3) C _2-4 alkynyl, Each of these groups may be substituted with from 1 to 5 substituents each independently selected from the group consisting of: (1) NR ³ R ⁴ , (2) a halogen atom, (3) CONR ⁵ R ⁶ (4) CO ₂ R ⁷ and (5) OR ⁸ ; R ³ and R ⁴ each independently represent (1) a hydrogen atom or (2) a C _1-4 alkyl group which may be OR ⁹ or CONR ¹⁰ R ¹¹ Replace; R ³ and R ⁴ may form, together with the nitrogen atom to which they are bonded, a 4 to 7 membered nitrogen-containing saturated heterocyclic ring which may be substituted with a keto group or a hydroxyl group; and R ⁵ and R ⁶ each independently represent (1) a hydrogen atom, (2) C _{1 -4} alkyl or (3) phenyl; R ⁷ represents (1) a hydrogen atom or (2) C _1-4 alkyl; R ⁸ represents (1) a hydrogen atom, (2) a C _1-4 alkyl group, ( 3) phenyl or (4) benzotriazolyl; R ⁹ represents (1) a hydrogen atom or (2) C _1-4 alkyl; R ¹⁰ and R ¹¹ each independently represent a (1) hydrogen atom or (2) C _1-4 alkyl; n represents an integer from 0 to 4; m represents an integer from 0 to 2; and when n is 2 or more, then R ¹ may be the same or different from each other.

In a preferred embodiment, the BTK inhibitor is a compound of formula (XX): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, preferably a hydrochloride salt thereof. The preparation of this compound is described in U.S. Patent Application Publication No. 2014/0330015 A1, the disclosure of which is incorporated herein by reference. In one embodiment, the BTK inhibitor is 6-amino-9-(1-(but-2-indenyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7 , 9-dihydro-8H-indol-8-one or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, or preferably the hydrochloride salt thereof. In one embodiment, the BTK inhibitor is 6-amino-9-[(3S)-1-(2-butylindolyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-dihydro-8H-indol-8-one or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, or a hydrochloride thereof.

The R-mirrogram isomer of formula (XX) is also known as ONO-4059 and is given by formula (XXI). In a preferred embodiment, the BTK inhibitor is a compound of formula (XXI): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, preferably a hydrochloride salt thereof.

In one embodiment, the BTK inhibitor is 6-amino-9-[(3R)-1-(2-butylindolyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)- 7,9-two Hydrogen-8H-indol-8-one or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, preferably the hydrochloride salt thereof.

The preparation of the formula (XXI) is described in the International Patent Application Publication No. WO 2013/081016 A1 and the U.S. Patent Application Publication No. 2014/0330015 A1, each of which is incorporated herein by reference. Briefly, BTK inhibitors of formula (XXI) can be prepared by the following procedure.

Step 1: A solution of benzhydrylamine (10.2 g) in dichloromethane (30 ml) was added dropwise to 4,6-dichloro-5-nitrate in dichloromethane (70 mL). A solution of a pyrimidine (10 g). Then triethylamine (14.4 ml) was added and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N,N-diphenylmethyl-6-chloro-5- Pyrimidine-4-amine (19.2 g).

Step 2: The compound prepared in Step 1 (19 g) and (3R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (10.5 g) were dissolved in dioxane (58 ml). Triethylamine (8.1 ml) was added and the mixture was stirred at 50 ° C for 5 hours. The reaction mixture was returned to room temperature, the solvent was evaporated, water was added and ethyl acetate was evaporated. The organic layer was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography to obtain (3R)-3-{[6-(diphenylmethylamino)-5-nitropyrimidin-4-yl]amino}pyrrolidin-1 - Tributyl carboxylic acid (27.0 g).

Step 3: A solution of the compound prepared in Step 2 (17.5 g) in ethyl acetate (360 mL) was added dropwise to the ice bath (23.3 g) A mixture of 3.0 M aqueous ammonium chloride solution (11.4 g) was used and the temperature immediately rose to room temperature. After stirring for 2 hours, the reaction mixture was filtered through CELITE and solvent was distilled off. The residue was purified by column chromatography to give (3R)-3-{[5-amino-6-(diphenylmethylamino)pyrimidin-4-yl]amino}pyrrolidin-1 - tert-butyl carboxylate (12.4 g).

Step 4: The compound prepared in Step 3 (8.4 g) and 1,1'-carbonyldiimidazole (5.9 g) were dissolved in tetrahydrofuran (120 ml) and the solution was stirred at 60 ° C for 15 hours. The solvent was distilled off from the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography to give (3R)-3-[6-(diphenylmethylamino)-8-keto-7,8-dihydro-9H-indole-9- Base] pyrrolidine-1-carboxylic acid tert-butyl ester (7.8 g).

Step 5: The compound (7.8 g) prepared in the step 4 will be dissolved in methanol (240 ml) and ethyl acetate (50 mL) was added 20% Lippmann (Pearlman)'s catalyst (Pd (OH) ₂ /C) (8.0 g, 100% by weight), subjected to hydrogen substitution and stirred at 60 ° C for 7.5 hours. The reaction mixture was filtered through CELITE and the solvent was distilled off to give (3R)-3-(6-amino-8-keto-7,8-dihydro-9H-indol-9-yl)pyrrolidin-1- Tert-butyl carboxylate (5.0 g).

Step 6: Add p-phenoxyphenylboronic acid (2.1 g), ketone (II) acetate (1.48 g), molecular sieve 4A (2.5 g) and pyridine (0.82 ml) at room temperature to prepare in step 5. A solution of the compound (2.5 g) in dichloromethane (200 mL) was then stirred for 21 hr. The reaction mixture Filtration by CELITE and purification of the residue by silica gel column chromatography to afford (3R)-3-[6-amino-8-keto-7-(4-phenoxyphenyl)-7,8 -Dihydro-9H-indol-9-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g).

Step 7: 4N HCl / dioxane (13 mL) was added to a EtOAc m. The mixture was stirred for 1 hour. The solvent is then distilled off to obtain (3R)-6-amino-9-pyrrolidin-3-yl-7-(4-phenoxyphenyl)-7,9-dihydro-8H-indole-8- Keto dihydrochloride (1.5 g).

Step 8: 2-butyric acid (34 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (78 mg), 1-hydroxyl After the benzotriazole (HOBt) (62 mg) and triethylamine (114 ml) were added to a solution of the compound (100 mg) prepared in Step 7 in dimethylformamide (3 ml), the mixture was Stir at room temperature for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium carbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate and evaporated. The residue was purified by thin layer chromatography (dichloromethane:methanol: 28% aqueous ammonia = 90:10:1) to afford 6-amino-9-[(3R)-1-(2-butenyl) -3-Pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-indole-8-one (formula (XXI)) (75 mg).

The hydrochloride salt of the compound of formula (XXI) can be prepared as follows: 6-amino-9-[(3R)-1-(2-butenyl)-3-pyrrolidinyl]-7-(4-phenoxy) Phenylphenyl)-7,9-dihydro-8H-indole-8-one (3.0 g) (which can be prepared as described above) was placed in a 300 ml 3-neck pear-shaped flask with ethyl acetate (30 m) L) and 1-propanol (4.5 ml) and the external temperature was set at 70 ° C (internal temperature 61 ° C). After confirming that the compound prepared in Step 8 was completely dissolved, 10% HCl/methanol (3.5 ml) was added, and after crystal precipitation was determined, the crystals were matured in the following order: temperature outside 70 ° C for 30 minutes, 60 ° C Outside the temperature for 30 minutes, 50 ° C outside the temperature for 60 minutes, 40 ° C outside the temperature for 30 minutes, room temperature for 30 minutes and ice bath for 30 minutes. The obtained crystals were filtered, washed with ethyl acetate (6 ml) and dried under vacuum at 50[deg.] C to afford white crystals of 6-amino-9-[(3R)-1-(2-butenyl)-3- Pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-indole-8-one hydrochloride (2.76 g).

In one embodiment, the BTK inhibitor is a compound selected from the structures disclosed in International Patent Application Publication No. WO 2013/081016 A1 and U.S. Patent Application Publication No. US 2014/0330015 A1, each of which is incorporated herein by reference. The contents are incorporated herein by reference.

In one embodiment, the BTK inhibitor is a compound of formula (XXII): Or a pharmaceutically acceptable salt, ester, solvate, hydrate, co-crystal or prodrug thereof, wherein: XYZ is NCC and has the presence of R ² , or is CNN and has no R ² present; R ¹ is 3 a member of the N-containing ring wherein N is unsubstituted or substituted with R ⁴ ; R ² is H or lower alkyl, especially methyl, ethyl, propyl or butyl; or R ¹ and R ² are together with their attached atoms forming 4-8 membered ring, preferably a 5-6 membered ring selected from unsubstituted or substituted with at least one substituent of LR ⁴ cycloalkyl group, a saturated or unsaturated heterocycle, aryl And heteroaryl ring; R ³ is independently halo, alkyl, S-alkyl, CN or OR ⁵ in each case; n is 1, 2, 3 or 4, preferably 1 or 2; L is a bond , NH, heteroalkyl or heterocyclic; R ⁴ is COR', CO ₂ R' or SO ₂ R', wherein R' is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl And a substituted or unsubstituted alkynyl group; R ⁵ is H or an unsubstituted or substituted heteroalkyl, alkyl, cycloalkyl, saturated or unsaturated heterocyclic group, aryl or heteroaryl. In some embodiments, the BTK inhibitor is one of the following specific embodiments of formula (XXII): X--Y--Z is C--N--N and no R ² is present; R ¹ is a ring of 3-8 members containing N, substituted by N of R ⁴ ; X--Y--Z is N--C--C and has the presence of R ² , and R ¹ is 3-8 members containing N Ring, substituted by N of R ⁴ ; and R ² is H or lower alkyl; X--Y--Z is N--C--C and has the presence of R ² ; and R ¹ and R ² are together with their attached atoms forming 4-8 membered ring selected from unsubstituted or substituted with at least one substituent group of LR ⁴ cycloalkyl, saturated or unsaturated heterocyclic, aryl and heteroaryl ring, wherein R Preferred rings for ¹ and R ² are 5-6 members, especially dihydropyrrole, tetrahydropyridine, tetrahydroindolizine, phenyl or pyridine; X--YZ is N--C--C and has R The presence of ² ; and R ¹ and R ² together with the atoms to which they are attached form a 5-6 membered ring, preferably (a) a phenyl substituted with a single -LR ⁴ , or (b) a dihydropyrrole or a piperidine, the substitution of a single -LR N ^4, wherein L is a bond; R ¹ is a piperidine or aza-spiro [3.3] heptane, preferably by substitution of R N ^4; R ⁴ is COR 'or SO ₂ R', especially wherein R' is a substituted or unsubstituted alkenyl group, Or a substituted or unsubstituted vinyl group; or R ⁵ is an unsubstituted or substituted alkyl or aryl group, especially a substituted or unsubstituted phenyl or methyl group, such as a cyclopropyl group A methyl group or a phenyl group substituted with a tetrabutyl group. In some embodiments, the BTK inhibitor is one of the following specific embodiments of formula (XXII): R ¹ is piperidine or azaspiro[3.3]heptane, substituted by N of R ⁴ , wherein R ⁴ is H, COR' or SO ₂ R', and R' is a substituted or unsubstituted alkenyl group, particularly a substituted or unsubstituted vinyl group; R ³ is -OR ⁵ and R ⁵ is benzene And n is 1; R ¹ and R ² together with the atoms to which they are attached form a 5-6 membered ring, preferably (a) a phenyl substituted with a single -LR ⁴ , or (b) a dihydropyrrole or Tetrahydropyridine, substituted with a single -LR ⁴ N, wherein L is a bond; R ³ is -OR ⁵ ; n is 1; R ⁴ is COR', and R' is a vinyl group; and R ⁵ is a phenyl group; X--YZ is C--N--N and no R ² is present; R ¹ is piperidine, substituted by N of R ⁴ ; R ³ is -OR ⁵ ; n is 1; R ⁴ is COR', and R' is an unsubstituted or substituted alkenyl group, especially a vinyl group; and R ⁵ is a substituted or unsubstituted aryl group, especially a phenyl group.

In a preferred embodiment, the BTK inhibitor is a compound selected from the group consisting of formula (XXIII), formula (XXIV), and formula (XXV):

Or their pharmaceutically acceptable salts, esters, solvates, hydrates, co-crystals or prodrugs. Formula (XXIV) is also known as BGB-3111. The preparation of such compounds is incorporated herein by reference in its entirety by reference to the entire disclosure of the entire disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of

Briefly, a BTK inhibitor of formula (XXIII) can be prepared by the following procedure.

Step 1: Preparation of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile:

A solution of 4-phenoxybenzoic acid (300 g, 1.4 mol) in SOCl ₂ (1.2 liter) was stirred at 80 ° C under N ₂ for 3 h. The mixture was concentrated in vacuo to give EtOAc m.

A solution of the intermediate (315 g) in toluene (800 mL) was added dropwise at 0-5 ° C over 2 hrs to &lt;RTI ID=0.0&gt;&gt; (350 g, 2710 mmol) solution. The resulting mixture was allowed to warm to RT and stirred for 16 hours. The reaction was quenched with water (2.0 liters) and extracted with EA (2.0 liters x 3). The combined organic layers were washed with 1000 ml 3N HCl solution, brine (2.0 liter × 3) washed, dried over Na ₂ SO ₄ dried and concentrated to give the crude product (330 g, 93%).

Step 2: Preparation of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile:

A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH (OMe ₃ ) (500 mL) was heated to 75 ° C for 16 h . The mixture was then concentrated to a residue and washed with EtOAc EtOAc (EtOAc) Nitrile.

Step 3: Preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile:

Add hydrazine hydrate (20 ml) to a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80 g, 290 mmol) in ethanol (200 mL) . The mixture was stirred at RT for 16 h then concentrated to give a crude material eluted with MeOH (30 <RTI ID=0.0> Oxyphenyl)-1H-pyrazole-4-carbonitrile.

Step 4: Preparation of 3-butyl (3-toluenesulfonyloxy) piperidine-1-carboxylate: Wherein 〝Boc〞 represents a third butoxycarbonyl protecting group.

TsCl (1.425 g, 7.5 mmol) was added to a solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.05 g, 5.0 mmol) in pyridine (8 mL). The mixture was stirred at RT and N ₂ for 2 days. The mixture was concentrated and partitioned between 100 mL EA and 100 mL EtOAc (1N). The organic layer from the aqueous layer was separated, saturated aqueous NaHCO ₃ (100 mL × 2), brine (100 mL × 3) washed and dried over Na ₂ SO _4. The organic layer was concentrated to give 1.1 g (60%) of 3-(t-toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.

Step 5: Preparation of 3-(5-Amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester :

Add Cs ₂ CO ₃ (650 mg, 2.0 mmol) to 3-(toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (355 mg, 1.0 mmol) in 5 mL DMF. And a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0 mmol). The toluenesulfonyloxy group is used in this reaction. The mixture was stirred at RT for 16 hours, at 75 ° C for 3 hours and at 60 ° C for 16 hours. The mixture was concentrated, washed with brine (100 mL×3) and dried over Na ₂ SO ₄ . The material was concentrated and purified on a silica gel column (purified with petroleum ether / ethyl acetate = 3 / 1) to afford 60 mg (13%) of 3-(5-amino) as a yellow oil. T-butyl 3-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.

Step 6: 3-(5-Amino-4-aminocarbamido-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Preparation:

Water (1 mL) and H ₂ O ₂ (1 mL) NaOH (200 mg, 5 mmol) was added to the DMSO 3- (5- amine (2 mL) and ethanol (2 ml) A solution of butyl 3-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.22 mmol) in. The mixture was stirred at 60 ° C for 15 minutes and concentrated to remove EtOH, followed by 10 mL water and 50 mL ethyl acetate. The organic layer was separated from the aqueous layer, washed with brine (30 mL×3) and dried over Na ₂ SO ₄ . After concentration, 50 mg of the residue was used directly in the next step, which was purified by preparative TLC (purified with petroleum ether / ethyl acetate = 1 / 1) to afford 12 as white solid. Mg (30%) 3-(5-Amino-4-amine-methylindolyl-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid Butyl ester.

Step 7: Preparation of 5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide:

Concentrated HCl (0.75 mL) was added to 3-(5-Amino-4-amine-carbamoyl-3-(4-phenoxyphenyl)-1H-pyrazole in ethyl acetate (1 mL) A solution of 1-butyl) piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol). The mixture was stirred at RT for 1 hour. Followed by addition of saturated NaHCO _3, until pH> 7 up, followed by addition of ethyl acetate (50 mL). The organic layer was separated from the aqueous layer, washed with brine (50 mL×3) and dried over Na ₂ SO ₄ . The resulting product was concentrated and purified by preparative TLC to (dichloromethane _{/ MeOH / NH 3 -H 2 O} = 5/1 / 0.01 elution), to be fed 10 mg (25%) of 5-amino-white solid 3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxamide.

Step 8: Preparation of 1-(1-propenylhydrylpiperidin-3-yl)-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide:

Pyridine (27 mg, 0.34 mmol) was added to 5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)- in dichloromethane (4 mL) 1H-pyrazole-4-carboxamide (63 mg, 0.17 mmol) in solution. A solution of propylene hydrazine chloride (12 mg, 0.17 mmol) in dichloromethane (1 mL) was then added dropwise. After stirring at RT for 4 hours, the mixture was partitioned between 100 mL of dichloromethane and 100 mL of brine. The organic layer was separated from the aqueous layer, washed with brine (100 mL×2) and dried over Na ₂ SO ₄ . The material was concentrated and purified by preparative TLC (methanol eluting with dichloromethane / MeOH = 10/1) to afford 4 mg (5.5%) of 1-(1-propenylhydrazin-3-yl) as a white solid. -5-Amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide.

The mirror image isomer of formula (XXIII) provided by the above procedure may be derived from 5-amino-3-(phenoxyphenyl)-1H-pyrazole-4-carbonitrile and (S)-3-hydroxypiperidone. The pyridine-1-carboxylic acid tert-butyl ester is prepared using a procedure similar to the formula (XXIV) (steps 4 to 8) or from (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester. The procedure of formula (XXV) (steps 4 to 8) is made. The racemic mixture of formula (XXIII) can be prepared by palmitic HPLC, crystallization of the palm salt or other means described above under suitable conditions generally recognized by those skilled in the art to provide a high image isomer purity formula ( XXIV) and formula (XXV).

In one embodiment, the BTK inhibitor is a compound selected from the structures disclosed in U.S. Patent Application Publication No. US 2015/0005277 A1, the disclosure of which is incorporated herein by reference.

In one embodiment, the BTK inhibitor is a compound selected from the structures disclosed in U.S. Patent No. 8,957,065, the disclosure of which is incorporated herein by reference. In one embodiment, the BTK inhibitor is HM-71224 (Hanmi Pharm. Co.) or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof. In one embodiment, the BTK inhibitor is N-(3-(2-(4-(4-methyl)) 1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-oxy)phenyl)propenylamine or a pharmaceutically acceptable salt, solvate, hydrate or eutectic thereof Or a prodrug. In one embodiment, the BTK inhibitor is N-(3-((2-(2-methoxy-4-(4-methyl)) 1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)propenylamine or a pharmaceutically acceptable salt, solvate or hydrate thereof , co-crystals or prodrugs.

In one embodiment, the BTK inhibitor is 7-propenyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazole [5',1 ':2,3] Imidazo[4,5-c]pyridine-3-carbamide or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof.

Other BTK inhibitors suitable for use in the methods, uses, and compositions of the present invention include, but are not limited to, those in, for example, International Patent Application Publication No. WO 2013/010868, WO 2012/158843, WO 2012/135944, WO 2012/135937 , U.S. Patent Application Publication Nos. 2011/0177011, 2014/0155385, 2014/0323464, and 2014/0045833, and U.S. Patent Nos. 8,501,751, 8,476,284, 8,008,309, 7,960,396, 7,825,118, 7,732,454, 7,514,444, 7,459,554, 7,405,295, and 7,393,848. Each of these disclosures is incorporated herein by reference.

Pharmaceutical composition

In some embodiments, the invention provides pharmaceutical compositions and methods for treating solid tumor cancer, lymphoma, leukemia, and blood cachexia.

In some embodiments, the invention provides a pharmaceutical composition for treating a BTK inhibitor of a disease associated with BTK activity, the diseases being selected from the group consisting of an inflammatory condition, a proliferative condition, and a cancer, including but not Limited to acute myeloid leukemia, chronic lymphocytic leukemia, rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, osteoarthritis, osteoarthritis, traumatic arthritis, pain Rheumatoid arthritis, Reiter's syndrome, polychondritis, acute synovitis, spondylitis, glomerulonephritis (with or without renal disease), autoimmune hematological disorders, hemolytic anemia, aplastic disorders Anemia, idiopathic thrombocytopenia and neutropenia, autoimmune gastritis and autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, host versus graft disease, Allograft rejection, chronic thyroiditis, Graves' disease, scleroderma, diabetes (types I and II), active hepatitis (acute and chronic), pancreatitis, primary biliary liver Hardening, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, sunburn, vasculitis (eg Behcet's disease) chronic renal insufficiency, Stefan - Stevens-Johnson syndrome, inflammatory pain, idiopathic steatorrhea, cachexia, sarcoma-like disease, Guillain-Barré syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease Pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, silicosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease, proliferative disease, Non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B cell diffuse large B-cell lymphoma (GCB-DLBCL , mantle cell lymphoma (MCL), B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia with mature B cells and B-cell lymphoma, proliferative mast cell disease, and multiple Myeloma-related bone disorders, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, increase Biological disease, non-Hodgkin's lymphoma, post-transplant lymphoproliferative disorder, hematologic cachexia, unexplained monogenic globulin, light chain amyloidosis, acute lymphoblastic leukemia, acute with mature B cells Lymphoblastic leukemia or B-cell lymphoma, proliferative mast cell disease, bone disorders associated with multiple myeloma, AIDS-related cancers (eg, lymphoma and Kaposi's sarcoma), virus-induced cancer, or Non-cancerous hyperproliferative disorders, such as single B cell lymphocytosis, benign hyperplasia of the skin (eg, psoriasis), restenosis, or benign prostatic hyperplasia (eg, benign prostatic hypertrophy (BPH)).

In some embodiments, the invention provides a pharmaceutical composition of a BTK inhibitor for treating solid tumor cancer, the cancer being selected from the group consisting of bladder cancer, squamous cell tumor, head and neck cancer Pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon tumor, breast tumor, breast cancer, fibrosarcoma, mesothelioma, renal cell tumor, tumor, thymoma, prostate cancer, colorectal cancer, ovarian cancer, Acute myeloid leukemia, thymic cancer, brain cancer, squamous cell carcinoma, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cancer, oropharyngeal cancer, stomach cancer, stomach cancer, cervical Cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-related cancer (eg lymphoma and Kaposi's sarcoma, virus-induced cancer (such as cervical cancer (human papilloma virus), B-cell lymphoproliferative disease, nasopharyngeal carcinoma (EB virus), Kaposi's sarcoma, and primary exudation Lymphoma (Kaposi's meat) Herpes virus), hepatocellular carcinoma (B hepatitis and hepatitis C virus) and T cells Cell leukemia (human T cell leukemia-1), glioblastoma, esophageal tumor, head and neck tumor, metastatic colon cancer, head and neck squamous cell tumor, ovarian tumor, pancreatic tumor, renal cell tumor, Hematological tumors, small cell lung cancer, non-small cell lung cancer, stage IV melanoma, and glioma.

The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a BTK covalent inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, as the active ingredient. When desired, the pharmaceutical composition comprises a pharmaceutically acceptable salt and/or a complex thereof and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluted Agents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. When desired, other agents may be admixed into the formulation or the two components may be formulated as separate formulations for simultaneous or combined use.

In some embodiments, the concentration of the BTK inhibitor provided in the pharmaceutical compositions and methods disclosed herein is independently less than, for example, 100%, 90%, 80%, 70% of the overall pharmaceutical composition or dosage form, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8% 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05 %, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of the BTK inhibitor provided in the pharmaceutical compositions and methods disclosed herein is independently greater than, for example, 90%, 80%, 70%, 60%, 50 of the overall pharmaceutical composition or dosage form. %, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50% 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3% 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06 %, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006% 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v.

In some embodiments, the concentration of the BTK inhibitor provided in the pharmaceutical compositions and methods disclosed herein is independently Within the scope of from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 3% of the total pharmaceutical composition or dosage form. 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22% From about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, about From 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12% or from about 1% to about 10% w/w, w/v or v/v.

In some embodiments, the concentration of the BTK inhibitor of the invention is independently within the range of from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% of the total pharmaceutical composition or dosage form. Up to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w/w, w/v or v/v.

In some embodiments, the dose or amount of the BTK inhibitor of the present invention is independently equal to or less than 10 grams, 9.5 grams, 9.0 grams, 8.5 grams, 8.0 grams, 7.5 grams, 7.0 grams, 6.5 grams, 6.0 grams, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g , 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 Gram, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g, which is present as an active ingredient in the overall pharmaceutical composition or dosage form.

In some embodiments, the dose or amount of the BTK inhibitor of the invention is independently greater than 0.0001 grams, 0.0002 grams, 0.0003 grams, 0.0004 grams, 0.0005 grams, 0.0006 grams, 0.0007 grams, 0.0008 grams, 0.0009 grams, 0.001 grams, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.008 g, 0.009 g, 0.0095 g 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 Grams, 0.095 grams, 0.1 grams, 0.15 grams, 0.2 grams, 0.25 grams, 0.3 grams, 0.35 grams, 0.4 grams, 0.45 grams, 0.5 grams, 0.55 grams, 0.6 grams, 0.65 grams, 0.7 grams, 0.75 grams, 0.8 grams, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 Grams, 8.5 grams, 9 grams, 9.5 grams or 10 grams are present as active ingredients in the overall pharmaceutical composition or dosage form.

The BTK inhibitors according to the invention are effective over a wide dosage range. For example, in the treatment of adults, independent from 0.01 per day To 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg, and in the range of doses from 5 to 40 mg per day are examples of dosages that can be used. The exact dose will depend on the amount of BTK resynthesis in any particular tissue compartment of the individual, and will also depend on the route of administration, the form in which the compound is administered, the sex and age of the individual to be treated, the weight of the individual to be treated, And the preferences and experience of the attending physician.

The efficacy of the compounds and compositions of the compounds described herein in the treatment, prevention, and/or management of the disease or condition to which they are adapted can be tested using various animal or human models known in the art.

Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

Pharmaceutical composition for oral administration

In some embodiments, the invention provides a pharmaceutical composition for oral administration comprising a BTK covalent inhibitor and at least one pharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceutical composition for oral administration comprising (i) an effective amount of a BTK inhibitor, and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition additionally contains (iii) an effective amount of another active compound.

In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical compositions of the present invention suitable for oral administration may be in discrete dosage forms such as capsules, cachets or lozenges, or in liquid or aerosol sprays, each containing a predetermined amount of powder or granules, The active ingredient of a solution or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion or a water-in-oil type liquid emulsion. These dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with carriers which comprise one or more essential ingredients. The composition is typically prepared by uniformly and intimately admixing the active ingredient with liquid carrier or finely divided solid carrier or both, and, if necessary, the product, if desired. For example, lozenges can be prepared by compression or molding, optionally with one or more accessory ingredients. The compressed lozenge can be in a free-flowing form (such as a powder or granule) which is optionally admixed with excipients such as, but not limited to, binders, lubricants, inert diluents and/or surfactants or dispersing agents. The active ingredient is prepared by compression in a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert diluent in a suitable machine.

The invention additionally comprises anhydrous pharmaceutical compositions and dosage forms, as water can contribute to the degradation of some of the compounds. For example, water (e.g., 5%) may be added to the medical technology as a means of simulating long-term storage to facilitate the determination of characteristics such as shelf life or stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the invention containing lactose can be made anhydrous if substantial contact with moisture and/or humidity is desired during manufacture, packaging, and/or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Accordingly, the anhydrous composition can be packaged using materials known to prevent exposure to water such that the composition can be contained within a suitable blending kit. Suitable packaging examples include, but are not limited to, sealed Foil, plastic or similar, unit dose containers, blister packs and strip packs.

A variety of BTK inhibitors can be used as the active ingredient and can be combined into a suitable blend according to conventional pharmaceutical compounding techniques and pharmaceutical carriers. The carrier can take a wide variety of forms depending on the form of preparation to be administered. In preparing the composition of the oral dosage form, any of the usual pharmaceutical media can be used as a carrier in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols, such as water. , glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like; or as carriers which can be used in the case of oral solid preparations, such as starch, sugar, microcrystalline cellulose, diluent, Granules, lubricants, binders and disintegrants, in some embodiments no lactose is used. For example, suitable carriers for oral solid preparations include powders, capsules and lozenges. If desired, the tablets can be coated with standard aqueous or non-aqueous techniques.

The composition may additionally comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, anti-adherents, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, colorants, odorants, Opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

The methods of the present invention can be accomplished by formulating the compositions into any suitable pharmaceutical dosage form to provide a variety of drug release profiles, including immediate release, sustained release, and delayed release. Various dosage forms in this regard are encompassed herein. These include, without limitation, pulsed release including the compositions of the invention Formulations wherein the individual doses of the therapeutic agent are released at repeated intervals; a delayed release (ER) formulation comprising a composition of the invention wherein the slow release therapeutic agent provides a therapeutic concentration of 8-12 hours; Controlled release (CR) formulations of the compositions of the invention wherein the therapeutic agent is released at a fixed rate; modified release (MR) formulations comprising the compositions of the invention (which provide selected time and/or position) Drug release characteristics to achieve therapeutic or convenience goals).

Thus, in some embodiments, the pharmaceutical dosage form is formulated to prevent release of the therapeutically active agent after administration until a predetermined interval has elapsed (timed release). In some embodiments, the pharmaceutical dosage form is formulated to provide for the almost continuous release of the therapeutically active agent (sustained release) over a predetermined period of time. In some embodiments, the pharmaceutical dosage form is formulated to provide for immediate release of the therapeutically active agent (immediate release) immediately after administration of the pharmaceutical composition.

In some embodiments, a pharmaceutical dosage form is formulated to pulsate a therapeutically active agent, wherein a single pharmaceutical dosage form provides an initial dose of the therapeutically active agent, followed by a non-release interval, after which a second dose of the therapeutically active agent is released The pulse of the therapeutically active agent (eg, pulsed release) may then be sequentially passed through one or more additional non-release intervals.

In some embodiments, a pharmaceutical dosage form formulated to provide a pulsed release is useful, for example, as a therapeutically active agent having a short half-life and having to be administered two or three times a day. In some embodiments, a pharmaceutical dosage form formulated to provide a pulsed release is used in a tissue or cell compartment to obtain a target BTK occupancy based on the BTK resynthesis rate. In some embodiments, a pharmaceutical dosage form formulated to provide pulsed release is used to demonstrate a therapeutically active agent of a first-pass effect (also known as a first-pass effect 〞 or a presystemic metabolism ,), for example, a large amount of metabolism before the therapeutic active agent reaches the systemic circulation and thus Significantly lower concentrations of therapeutically active agents. In some embodiments, a pharmaceutical dosage form formulated to provide a pulsatile release has an active agent that is lost when the desired therapeutic effect is maintained while maintaining a fixed blood content. In some embodiments, a pharmaceutical dosage form formulated to provide a pulsed release has a therapeutically useful agent for reducing the likelihood of abuse of a particular type of therapeutically active agent, such as tolerance, addiction, and deliberate overdose.

Any of the pharmaceutical dosage forms disclosed herein can be administered to an individual via any suitable route of administration, including, but not limited to, orally, rectal, nasal, pulmonary, epidural, ocular, intra-orbital, intra-arterial, intracardiac, Intraventricular, intradermal, intravenous, intramuscular, intraperitoneal, intraosseous, intrathecal, intravesical, subcutaneous, topical, transdermal, transmucosal, sublingual, buccal, vaginal and inhalation routes of administration. In some preferred embodiments, delivery routes for MR formulations include, without limitation, injections, implants, topical plasters, lozenges, capsules, ovules, suppositories, films, vaginal rings, tampon, and osmotic pump systems. .

In a preferred embodiment, the pharmaceutical dosage form of the invention is a controlled release pharmaceutical formulation comprising a core comprising a compound of the invention and a coating layer on the surface of the core. In some embodiments, the pharmaceutical dosage form comprises an immediate release core comprising a therapeutic agent and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical dosage form comprises an envelope on the immediate release core surface comprising a rate controlling polymer. Any suitable The combined rate controlling polymer can be used in the dosage form of the present invention. In some preferred embodiments, examples of rate controlling polymers include, without limitation, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methylcellulose. , ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, sodium carboxymethyl cellulose; acrylic polymers and copolymers, preferably from Acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins; vinyl polymers and copolymers, such as polyvinyl Pyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, ethylene-vinyl acetate copolymer; enzyme degradable polymer such as azo polymer, pectin, polyglucosamine , amylase, guar gum, zein, shellac or a combination thereof.

In some embodiments, examples of rate controlling polymers include, without limitation, cellulose acetate, cellulose triacetate, agar acetate, starch triacetate, beta polyglucose acetate, acetaldehyde. Dimethyl acetate, cellulose acetate methyl carbamate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate dimethyl acetate, cellulose acetate Ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate butyl sulfonate, cellulose acetate propionate, poly(vinyl methyl ether) Copolymer, cellulose acetate butyl sulfonate, cellulose acetate octanoate, cellulose acetate laurate, cellulose acetate p-toluene sulfonate, locust bean gum triacetic acid Ester, hydroxylated ethylene-vinyl acetate, cellulose acetate butyrate, ethyl cellulose, and combinations thereof.

In some embodiments, the controlled release formulation comprises a multilayered inner core and/or a multilayered envelope.

Examples of pulsatile release formulations which may be suitable for use in the compositions of the present invention include, but are not limited to, those described in the following: U.S. Patent Nos. 5,413,777, 5,260,068, 4,777,049, 5,391,381, 5,472,708; The disclosure of WO 97/32424 is incorporated herein by reference.

In a preferred embodiment, the pharmaceutical dosage form of the invention is a sustained release solid dosage form. Examples of sustained release solid dosage forms include, but are not limited to, those described in U.S. Patent Nos. 6,056,977, 8,277,840, 4,690,682, 5,767,153, 4,889,721, 4,753,801, 5,773,031, 6,197,344, 7,422,758, 5,480,868, 6,087,324, 4,261,970, 4,869,904, 3,344,029,6,852,724,4,178,361,2,951,792,3,065,143,4,837,032,6,376,461,8,067,020,7,323,169,5,136,968,8,920,837,5,330,767,3,901,969,6,528,093,4,765,990,6,355,236,6,503,911,3,911,100,3,147,187,2,805,977,7,838,032,5,261,896,6,011,011,5,593,694,8,197,846, 4,968,508, 5,002,774, 5,601,844, 6,007,843, 4,990,340, 6,458,387, 4,988,679, 7,179,490, 3,901,968, 3,374,146, 5,238,686, 6,426,091, 4,781,919, 3,773,920, 7,662,408,8,470,359,5,972,891,8,197,839,8,877,242,6,756,049,8,992,979,5,688,530,6,447,796,8,034,379,7,883,718,7,838,024,8,361,052,6,991,808,7,833,545,8,921,326,8,529,542,6,964,781,6,506,410,6,756,058,8,318,210,5,795,882,6,419,961,8,012,508,6,410,052, 6,740,634, 4,889,720, 7,884,071, 8,574,613, 7,820,200, and 4,845,123; and International Patent Application Publication Nos. WO 2011/162413, 2011/078394, 2006/032089, 2005/117934, 2003/002102, 2005/123120, 2003/009833, 2012/ 063257, 2003/061634, 2003/009800, 2010/007623, 2003/051335, 2011/007353, 2013/024051, 2001/012233, 2001/072318, 2014/078486, 2007/147861, 2001/005430, 2002/026214, 2003/022242, 1998/032423, 2006/116565, 2006/116565, 2014/147526, 2003/009829, 2007/115033, 2007/115033, 2008/022146, 2008/022146, 2008/058288, 2008/058288, 2015/ 021153, 2008/075762, 2011/094431, 2012/003479, 2010/075072, 2013/173657, 2009/060322, 2010/102071, 2006/093838, 2006/093838, 2006 /004167, 1998/029105, 2003/002091, 2011/024168, 2015/025312, 2014/036534, The disclosures of these disclosures are hereby incorporated by reference in its entirety by reference in its entirety in the the the the the the the the the the the the the the the the the the the the the the the

Examples of immediate release formulations which may be suitable for use in the compositions of the present invention include, but are not limited to, those described in U.S. Patent Nos. 7,108,859, 8,895,058, 4,674,480, 8, 580, 298, 9, 011, 905 and 8, 197, 839; No. US 2014/0066447, 2007/0141140, 2006/0275365, and 2007/0059359; and International Patent Application Publication Nos. WO 2013/064900, 2004/073592, 2006/131394, and 2006/131393, the disclosures of which are incorporated herein. This article is for reference.

Examples of delayed release formulations that may be suitable for use in the compositions of the present invention include, but are not limited to, those described in U.S. Patent Nos. 5,108,758, 7,105,174, 7,108,859, 6,677,319, 8,883,201, and 7,704,977; Case No. US 2002/0004070, 2003/0104054, 2003/0104058, 2014/0100283, 2010/0022480, 2008/0193590, 2010/0247640, 2007/0238707, 2007/0292512, 2007/0148228, 2008/0311223, 2010/0203163 , 2006/0280795, 2011/0287094 and 2009/0324741; and International Patent Application Publication Nos. WO 1989/011269, 2015/089326, 2004/012717, 2007/117706, 2007/146234, 2011/107755, 2008/151433 and 2014 /130678.

In some preferred embodiments, the pharmaceutical dosage form comprises a volume The unit dose contained in the closed capsule. In some preferred embodiments, the pharmaceutical dosage form comprises a compressed lozenge. In some preferred embodiments, the pharmaceutical dosage form comprises a single lozenge in which the unit dose containing the drug presents a complete but discrete fragment. In some preferred embodiments, the pharmaceutical dosage form comprises drug-containing particles or beads. Drug-containing particles or beads (wherein the drug-containing particles or beads refer to an inert carrier coated with a drug, such as a lactose bead coated with a drug) can release the drug almost immediately after ingestion of the dosage form or along a continuous Release profile or delayed release profile travel.

In some embodiments, a pharmaceutical dosage form comprises individual unit doses that are compressed into a single lozenge and present a complete but discrete fragment (eg, a layer) thereof. For example, the drug-containing particles or drug-containing beads can be compressed together into a single tablet using conventional ingot methods.

Pharmaceutical composition for injection

In selected embodiments, the invention provides a pharmaceutical composition for injection comprising a BTK covalent inhibitor and a pharmaceutical excipient suitable for injection. The components and amounts of the agents in the composition are as described herein.

Forms which may be incorporated into the compositions of the invention for injection administration include aqueous or oily suspensions or emulsions (with sesame oil, corn oil, cottonseed oil or peanut oil), as well as elixirs, mannitol, dextrose or sterile aqueous solutions, And similar pharmaceutical agents.

Aqueous solutions in saline are also known for injection. Ethanol, glycerin, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils can also be used. Appropriate liquidity can be exemplified As used in the case of dispersions, a coating agent (such as lecithin) that maintains the desired particle size is used and maintained by the use of a surfactant. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

Sterile injectable solutions are prepared by incorporating the requisite amount of the BTK inhibitor together with various other ingredients such as those listed above in a suitable solvent, followed by filter sterilization if desired. Dispersions are typically prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing base dispersion medium and those ingredients from those enumerated above. In the case of a sterile powder for the preparation of a sterile injectable solution, the particular desired method of preparation is a vacuum drying and freeze drying technique which yields a powder of the active ingredient plus any additional desired ingredients from its previously sterilely filtered solution. .

Other pharmaceutical compositions

The pharmaceutical composition may also be administered from the compositions described herein and one or more pharmaceutically acceptable agents suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or spinal administration. Prepared by the agent. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds. Handbook of Clinical Drug Data, Eleventh Edition, McGraw-Hill, 2010.

The administration of a BTK covalent inhibitor or a pharmaceutical composition of such compounds can be accomplished by any method that enables delivery of the compound to the desired tissue compartment. These methods include oral route, intraduodenal route, parenteral route (This includes intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal administration), rectal administration, local delivery by catheter or stent, or by inhalation. Combinations of compounds can also be administered intra-fat or intrathecally.

The invention also provides kits. The kit includes BTK covalent inhibitors in a suitable package and written information that may include instructions, clinical studies, and side effects. Such kits may also include information such as scientific literature bibliographies, package inserts, clinical trial results and/or summaries of such information and the like, which indicate or establish the activity and/or advantages of the composition, and / or instructions for administration, administration, side effects, drug interactions, or other information useful to health care providers. Such information can be based on a variety of research results, such as studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may additionally contain another dose. In selected embodiments, the BTK inhibitor and the other agent are provided as separate compositions in separate containers within the kit. In selected embodiments, the BTK inhibitor and the other agent are provided as a single composition in a container in the kit. Suitable packaging and additional articles of use (e.g., measuring cups for liquid formulations, foil wrappers that minimize exposure to air, and the like) are known in the art and can be incorporated into kits.

BTK occupation and resynthesis

The BTK occupancy (or BTK target occupancy) measures the amount of BTK enzyme that has covalently bound to the BTK inhibitor on the active site kinase. Methods for measuring BTK occupancy in B cell lysates include, for example, the use of biotin Linked selective probe molecules or other probes that can be used for detection in various assay platforms. In the case of a biotin-labeled occupancy probe, the target occupies a streptavidin immunosorbent assay that can bind to the biotinylated probe molecule and the BTK protein and is assayed using streptavidin coated Standard enzyme-linked immunosorbent assay (ELISA) method for layout, as described, for example, in Evans et al., J. Pharmacol. Exp. Ther. 2013, 346, 219-228, or after capture with antibodies against BTK Detection with streptavidin conjugated to the enzyme or probe used for detection. When a properly standardized method is used, the BTK occupancy can be reported as a percentage of BTK that is effectively covalently bound, with 100% occupancy indicating that all of the BTKs are covalently bound. BTK can also be reported as free BTK for total protein per mass (eg, picogram free BTK/microgram total protein or nanogram free BTK/microgram total protein), or free BTK percentage that can be effectively detected by BTK active site probes. . Other methods suitable for determining BTK occupancy are described in U.S. Patent Application Publication No. US 2015/0260723 A1, the disclosure of which is incorporated herein by reference.

In one embodiment, the invention provides a method of treating a condition caused by cellular BTK activity (i.e., a condition mediated by BTK) comprising administering a dose effective to obtain a BTK selected from the group consisting of: Step of BTK covalent inhibitor: greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99 %. In one embodiment, the invention provides a method of treating a condition mediated by BTK, wherein the condition is cancer, the method comprising administering an effective acquisition selected from the group consisting of The steps of BTK inhibitors occupied by BTK of the following group: greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, More than 98% and greater than 99%.

In one embodiment, the invention provides a method of treating a condition mediated by BTK comprising the step of administering a BTK inhibitor effective to obtain a dose selected from the group consisting of: averaging BTK: 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% and 100%. In one embodiment, the invention provides a method of treating a condition mediated by BTK, wherein the condition is an inflammatory, immune or autoimmune disease, the method comprising administering an average of an average selected from the group consisting of The step of the BTK inhibitor at the dose of BTK: about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, and about 99%.

In one embodiment, the invention provides a method of treating a condition BTK-mediated, comprising the step of administering a BTK inhibitor effective to obtain a dose selected from the group consisting of BTK: between 80% and Between 85%, between 82.5% and 87.5%, between 85% and 90%, between 87.5% and 92.5%, between 90% and 95%, between 92.5% and Between 97.5% and between 95% and 100%. In one embodiment, the invention provides a method of treating a condition BTK-mediated, comprising the step of administering a BTK inhibitor effective to obtain a dose selected from the group consisting of BTK: between 95% and 97% Between 96% and 98%, between 97% and 99%, and between 98% and 100%.

BTK resynthesis refers to the process of producing new BTK enzymes after the existing BTK enzymes are occupied by covalent attachment to BTK inhibitors. This process may occur in living cells over time, or may occur during the period of time when new cells are produced during proliferation or from the tissue chamber of interest (eg, bone marrow) to the assay chamber. The BTK resynthesis rate can be measured by measuring the BTK occupancy over a period of time in a particular chamber; or by sampling a sample taken from a chamber of interest at a particular time after administration of the fully occupied dose of the BTK covalent inhibitor. The free BTK present in the measurement. The BTK resynthesis rate can also be obtained at an average rate.

The BTK resynthesis rate can be determined by BTK inhibitor occupancy data fitting a suitable biochemical kinetic pattern. For example, if the target occupancy assay determines free protein and assumes full occupancy of the protein after administration, free BTK can be determined after administration by pharmacokinetic-pharmacodynamic (PK/PD) mode, which is estimated to be BTK. The resynthesis rate is occupied by the BTK target at t1/2 of the function. Another method uses the following formula: free BTK = new BTK / h * h (where h is the hour) or linear extrapolation of the applied data to observe the decline during the washout period after administration of the BTK inhibitor The BTK target occupies and restores the BTK messaging function. The latter method assumes a linear synthesis rate of BTK over time, while the former method is more nuanced and predicts the first or second stage terminal elimination period occupied by the BTK target. The target occupancy assay can be performed such that free BTK is not an absolute value, but is based on 100% free BTK in the individual prior to administration. 100% The BTK occupancy value was determined by incubating the same test sample with a high dose of exogenous BTK covalent inhibitor. The BTK resynthesis rate (new BTK/hour) can be expressed in % per hour, expressed as a percentage of free BTK before administration. Alternatively, if the performance of the BTK protein is quantified, the BTK resynthesis rate can be quantified in picograms per microgram of tissue per hour or picogram per microgram of total protein per hour.

In one embodiment, the invention includes a method of treating cancer, a method of treating an inflammatory, immune, and autoimmune disease, and a method of inhibiting an immune response of an organ or a cell transplant, wherein the cancer, disease, or immune response is to be inhibited Showing a BTK resynthesis rate that can be used at the disease site to detect specific imaging agents present in the unoccupied BTK target site with CT scans, positron emission tomography (PET) imaging, magnetic resonance imaging (MRI) or When measured by a combination of near-infrared fluorescence imaging or other in vivo imaging modalities, the method is a tailored treatment for a particular disease based on the rate of BTK regeneration in a diseased tissue. In one embodiment, the PET probe is an ¹¹ C-labeled BTK inhibitor. In one embodiment, the PET probe is an ¹¹ C-labeled BTK inhibitor. In one embodiment, the PET probe is an ¹¹ C-labeled BTK inhibitor, such as a BTK inhibitor of formula (I) to (XXV) labeled at a specific carbon position, such as an exocyclic carbon position. It can be made by synthetic methods generally known to those skilled in the art. In one embodiment, the PET probe is an ¹⁸ F-labeled BTK inhibitor, such as a BTK inhibitor of formula (I) to (XXV), wherein hydrogen is substituted with a ¹⁸ F core, such as at an aryl position. Instead, it can be made by synthetic methods generally known to those skilled in the art. The preparation of organic molecules containing ¹¹ C, ¹⁸ F, ¹³ N and ¹⁵ O labels for PET imaging is described, for example, in Miller et al., Angewandte Chemie Int. Ed., 2008, 47, 8998-9033.

In one embodiment, the BTK resynthesis rate is selected from the group consisting of: about 0.1 picograms free BTK per microgram total protein per hour, about 0.5 picograms free BTK per microgram total protein per hour, about 1 skin. Gram free BTK / microgram total protein / hour, about 2 picograms free BTK / microgram total protein / hour, about 3 picograms free BTK / microgram total protein / hour, about 4 picograms free BTK / microgram total protein / hour, about 5 picogram free BTK / microgram total protein / hour, about 6 picograms free BTK / microgram total protein / hour, about 7 picograms free BTK / microgram total protein / hour, about 8 picograms free BTK / microgram total protein / hour , about 9 picograms free BTK / microgram total protein / hour, about 10 picograms free BTK / microgram total protein / hour, about 20 picograms free BTK / microgram total protein / hour and about 50 picograms free BTK / microgram total protein /hour.

In one embodiment, the BTK resynthesis half-life is selected from the group consisting of: 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 Hours, 22 hours, 24 hours, 48 hours, and 72 hours.

Different BTK resynthesis rate cancers in different tissues

Leukemias and lymphomas can display different BTK resynthesis relative rates in B cells such as bone marrow, lymph nodes, and blood. Producing many B cell subsets in the human body, as in Perez-Andres et al. Cytometry B (Clinical Cytometry), 2013, 78B (Suppl. 1), S47-S60 and Allman et al. Curr. Opin. Immunol. 2008, 20, 149-157. For example, follicular B cells can mature in both bone marrow and spleen and can occupy at least two different ecological locations. Certain B cell subsets can circulate between different tissue compartments by surrounding blood. The tissue chamber includes secondary lymphoid tissues (such as lymph nodes and mucosa-associated lymphoid tissues), bone marrow, and spleen, as in Perez-Andres et al., Cytometry B (Clinical Cytometry), 2013, 78B (Suppl. 1), S47-S60. Said. Other tissue compartments may include sites of primary or metastatic disease, such as occurring in primary central nervous system lymphoma, primary testicular lymphoma, and mucosal associated lymphoid tissue (MALT) lymphoma. The knowledge of these ventricular circulation by tumor cells carrying BTK is of importance in the effective treatment of immune and lymphoproliferative diseases such as leukemia. The BTK target occupancy and resynthesis rate (or half-life) of different tissue chambers of interest can be determined using established sampling techniques such as blood draw, fine needle draw, and bone marrow biopsy.

The approximate absolute value of BTK occupancy can be measured using methods such as those described in J. Pharmacol. Exp. Ther. 2013, 346, 219-228 by Evans et al. Other methods of measuring BTK occupancy can also be used to properly calibrate the total BTK in the sample, such as the Western blotting process described in Advani et al., J. Clin. Oncol. 2013, 31, 88-94. The BTK resynthesis rate can also be assessed using a pulse tracking method (also known as pulse tracking analysis). The pulse-tracking method utilizes a cell pulsed exposure to a labeled compound (eg, a radiolabeled amino acid), which is incorporated into the BTK protein by the cell, followed by exposure of the cell to an unlabeled compound. As a tracer, the labeled BTK protein can then be followed until it degrades. Pulses can also be achieved using labeled BTK covalent inhibitors (such as radiolabeled formula (II)), followed by tracking degradation of the protein-BTK inhibitor product. Suitable pulse tracking methods are described, for example, in Jansens and Braakman, Pulse-Chase Labeling Techniques for the Analysis of Protein Maturation and Degradation, In Protein Misfolding and Disease (Methods in Molecular Biology), Vol. 232, 2003, pp. 133-145. .

In one embodiment, the invention includes a method of treating leukemia that exhibits a different rate of BTK resynthesis in malignant cells in at least two different tissue chambers. Such leukemias include chronic lymphocytic leukemia, small lymphocytic lymphoma, anterior lymphocytic leukemia, pre-myeloid leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma or B-cell acute lymphoblastic leukemia.

In one embodiment, the BTK resynthesis ratio between the two tissue chambers is selected from the group consisting of: 0.01 to 1, 0.1 to 1, 0.5 to 1, 1 to 1, 1 to 1.5, 1 To 2, 1 to 5, 1 to 10 and 1 to 100. Among the peripheral blood B cells of healthy volunteers treated with BTK covalent inhibitors, those with doses that caused incomplete BTK targets had higher BTK resynthesis rates, as exemplified in FIG. In contrast, in the tissue compartment containing CLL tumor cells, those treated with 100 mg QD had higher rates of BTK resynthesis compared to those after 100 mg BID dose. The focus is on administration of 100 mg BID for 8 days (ie in steady state, Figure 34) in the CLL tumor cell compartment. The rate of resynthesis was similar to that observed in normal B lymphocytes from healthy volunteers. Because treatment with BTK inhibitors induces B lymphocytes (including CLL tumor cells) to be released from tissues into the peripheral blood (see Advani et al., J. Clin. Oncol. 2013, 31, 88-94), in the blood. A BTK resynthesis rate element was observed to facilitate the transport of the surrounding (tissue-based) lymphocytes to the central chamber.

Dosage and drug delivery configuration

The amount of BTK inhibitor administered will depend on the individual to be treated, the severity of the condition or condition, the rate of administration, the handling of the compound, and the discretion of the prescribing physician. The BTK resynthesis rate and the desired percent inhibition of BTK function in the target cells/tissue of the disease set and disease subsets within each disease setting also affect the amount of BTK inhibitor administered. However, an effective dose is a single or divided dose in the range of from about 0.001 to about 100 mg/kg body weight per day, such as from about 1 to about 35 mg/kg/day. For a 70 kg person, the amount can be equivalent to about 0.05 to 7 grams per day, such as from about 0.05 to about 2.5 grams per day. In some instances, a dose value below the lower limit of the foregoing range may be more appropriate, although in other examples larger doses may be used without causing any deleterious side effects - for example by dividing the larger dose into Several small doses are administered throughout the day.

In one embodiment, the BTK inhibitor is administered in a single dose. This administration is usually by injection for rapid introduction of the agent - for example by intravenous injection. However, other approaches may be used where appropriate. A single dose of BTK inhibitor can also be used to treat acute conditions.

In selected embodiments, BTK inhibitors are administered in multiple doses. Administration may be once, twice, three times, four times, five times, six times or more than six times a day. Administration may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, the administration of the BTK inhibitor is about once a day to about 6 times a day. In another embodiment, the BTK inhibitor is administered continuously for no more than about 7 days. In yet another embodiment, continuous administration is for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some instances, continuous administration is achieved and maintained as necessary.

BTK inhibitors can be administered continuously as long as necessary. In selected embodiments, the BTK inhibitor is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the BTK inhibitor is administered less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the BTK inhibitor is administered on an ongoing basis - for example, for the treatment of chronic effects.

An effective amount of the inhibitor can be administered in a single or multiple doses, including transrectal, buccal, intranasal, and transdermal routes, by any of the accepted modes of administration of a similarly useful agent. Intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

An effective amount of a BTK inhibitor can be determined according to the aspect of the invention by comparing and interpreting BTK occupancy or BTK resynthesis rate obtained from B cells in different tissue compartments. In one embodiment, leukemia (which includes chronic lymphocytic leukemia, small lymphocytic lymphoma, pre-dip Pascal leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, or B-cell acute lymphoblastic leukemia) between tumor cells in the blood and tumor cells in the tissue chamber (which includes lymph nodes and bone marrow) Showing different BTK occupancy or BTK resynthesis rates, wherein the BTK occupancy or BTK resynthesis rate in the tissue compartment is relatively large, the difference amount being selected from the group consisting of at least 10%, at least 15%, at least 20% At least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In one embodiment, leukemia (including chronic lymphocytic leukemia, small lymphoblastic lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or B-cell acute lymphoblastic leukemia) tumor in the blood Cells exhibit different rates of BTK occupancy or BTK resynthesis between tumor cells in the tissue compartment (which includes lymph nodes, bone marrow, and primary and/or metastatic lymphoma sites), where BTK occupancy in the tissue compartment or The BTK resynthesis rate is relatively large, and the difference amount is selected from the group consisting of 0 to 10%, 10 to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100%.

In one embodiment, the invention comprises a method of treating leukemia in a leukemic bone marrow B cell that exhibits a higher rate of BTK resynthesis than a BTK resynthesis rate in leukemia blood B cells, comprising administering a compound dose a step of reducing the rate of BTK resynthesis, wherein the compound is selected from the group consisting of: (I), (II), (III), Formula (IV), Formula (V) and Formula (VI) or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, wherein the dosage is administered once a day Twice a day or three times a day, and the leukemia is chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma or mantle cell lymphoma.

In one embodiment, the invention comprises a method of treating leukemia in a leukemic bone marrow B cell that exhibits a higher rate of BTK resynthesis than a BTK resynthesis rate in leukemia lymph node B cells, comprising administering a compound dose a step of reducing the rate of BTK resynthesis wherein the compound is a pharmaceutically acceptable salt of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or a eutectic, hydrate, solvate or prodrug wherein the dosage is administered once daily, twice daily or three times daily, and wherein the leukemia cancer is chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse Large B-cell lymphoma or mantle cell lymphoma.

In one embodiment, the invention comprises a method of treating a leukemia resynthesis rate in blood B cells of acute leukemia that is higher than a rate of BTK resynthesis in blood B cells of chronic leukemia, comprising administering a compound Dosage to reduce the rate of BTK resynthesis wherein the compound is of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or pharmaceutically acceptable A salt, co-crystal, hydrate, solvate or prodrug wherein the dosage is administered once daily, twice daily or three times daily, and wherein the leukemia cancer is B cell acute lymphoblastic leukemia.

Method of treating cancer

In some embodiments, the invention provides a method of treating a hyperproliferative disorder in an individual, wherein the hyperproliferative disorder is cancer. In one embodiment, the individual is a mammal. In one embodiment, the individual is a human. In one embodiment, the individual is a mammal, wherein the mammal is a companion animal, such as a canine, feline or equine.

In some embodiments, the invention provides a method of treating cancer in a human subject, wherein the cancer is leukemia, lymphoma or solid tumor cancer, the method comprising medicinally administering a therapeutically effective amount of a BTK inhibitor or a BTK inhibitor The step of administering the salt, ester, prodrug, solvate, co-crystal or hydrate to the individual. In some embodiments, the invention provides methods of treating cancer selected from the group consisting of non-Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia (CLL), small lymphoid spheroids Lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic Leukemia, Burkitt's leukemia, juvenile bone marrow monocystic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous Epithelial cell carcinoma, skin cancer, melanoma, eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head Cancer, neck cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (such as metastatic bone cancer), esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central Nervous system cancer, acquired immunodeficiency syndrome-associated cancer (eg, lymphoma and Kaposi's sarcoma), virus-induced cancer, such as cervical cancer (human papillomavirus), B-cell lymphoproliferative disease, and nasopharyngeal carcinoma (EB virus), Kaposi's sarcoma and primary exudative lymphoma (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C virus) and T-cell leukemia (human T-cell leukemia) Virus-1) or mastocytosis. In some embodiments, the invention provides methods of treating a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or a condition of a prostate (eg, benign prostatic hypertrophy (BPH)) . In some embodiments, the invention provides methods of treating a proliferative disorder in cells of the bone marrow system, such as acute myeloid leukemia and chronic myelogenous leukemia.

In one embodiment, the invention provides a method of treating a CLL subtype of a human comprising administering a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, co-crystal, solvate thereof, or The step of administering hydrate to a human individual. Many subtypes of CLL have been characterized. CLL can be classified by immunoglobulin heavy chain variable region (IgV _H ) mutation status in leukemia cells. Damle et al., Blood, 1999, 94, 1840-47; Hamblin et al., Blood 1999, 94, 1848-54. Patients with IgV _H mutations usually live longer than patients who do not have IgV _H mutations. ZAP70 expression (positive or negative) was also used to characterize CLL. Rassenti et al., N. Engl. J. Med. 2004, 351, 893-901. ZAP-70 methylation on CpG3 is also used to characterize CLL, for example by pyrosequencing. Claus et al., J. Clin. Oncol. 2012, 30, 2483-91; Woyach et al., Blood 2014, 123, 1810-17. CLL is also classified by disease stage under the Binet or Rai criteria. Binet et al., Cancer 1977, 40, 855-64; KRRai, T. Han, Hematol. Oncol. Clin. North Am. 1990, 4, 447-56. Other common mutations (such as 11p deletion, 13q deletion, and 17p deletion) can be assessed using well-known techniques, such as fluorescence in situ hybridization (FISH). In one embodiment, the invention provides a method of treating CLL in a human comprising comprising a therapeutically effective amount of a BTK inhibitor of formula (II), or a pharmaceutically acceptable salt or ester thereof, a prodrug, a co-crystal, a solvent The step of administering the compound or hydrate to the human body, wherein the CLL line is selected from the group consisting of IgV _H mutation-negative CLL, ZAP-70-positive CLL, CLL-positive CAP-70 methylated CLL, CD38-positive CLL, chronic lymphocytic leukemia characterized by 17p13.1 (17p) deletion and CLL characterized by 11q22.3 (11q) deletion.

In one embodiment, the invention provides a method of treating CLL in a human comprising comprising a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, co-crystal, solvate or hydrate thereof The step of administering to the mammal, wherein the CLL undergoes a Richter transformation. Methods for assessing the Rickert's transformation (also known as Richter's syndrome) are described in Jain and O'Brien, Oncology, 2012, 26, 1146-52. The CLL subtype observed in the 5-10% of patients of the Ricker. It involves the development of invasive lymphoma from CLL and usually has a poor prognosis.

In one embodiment, the invention provides a method of treating a hematological malignancy in a human comprising comprising a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, co-crystal, solvate thereof or The step of administering hydrate to the human body. Hematological malignancies include CLL and SLL, as well as other blood cancers, include B-cell malignancies. In one embodiment, the invention relates to a method of treating a human hematological malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), Waldenstrom's macroglobulinemia WM), Burkitt's lymphoma, multiple myeloma or spinal fibrosis, the method comprising administering a therapeutically effective amount of a BTK inhibitor or a pharmaceutically acceptable salt, ester, prodrug, co-crystal thereof , a solvate or a hydrate step. In one embodiment, the invention is directed to a method of treating an NHL selected from the group consisting of painless NHL and invasive NHL, the method comprising administering a therapeutically effective amount of a BTK inhibitor or a pharmaceutically acceptable amount thereof a step of a salt, ester, prodrug, co-crystal, solvate or hydrate.

In one embodiment, the invention provides a method of treating a DLBCL selected from the group consisting of diffuse large B-cell lymphoma (DLBCL-ABC) and germinal center B-cells that act like activated B-cells Diffuse large B-cell lymphoma (DLBCL-GCB) comprising administering a therapeutically effective amount of a BTK inhibitor or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof step.

In one embodiment, the invention provides a method of treating MCL selected from the group consisting of a coat of MCL, a nodular MCL, a diffuse MCL, and a maternal MCL (also known as a parental cell variant MCL). The method comprises administering a therapeutically effective amount of a BTK inhibitor or a physician thereof A step of a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate.

In one embodiment, the invention provides a method of treating a B-ALL selected from the group consisting of: early pre-B-cell B-ALL, pre-B-cell B-ALL, mature B-cell B-ALL (also known as B-ALL) For Burkitt's leukemia and pro-lymphocytic leukemia, the method comprises administering a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof step.

In one embodiment, the invention provides a method of treating Burkitt's lymphoma selected from the group consisting of sporadic Burkitt's lymphoma, regional Burkitt's lymphoma, and human immunodeficiency A virus-associated Burkitt's lymphoma, the method comprising the step of administering a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof.

In one embodiment, the invention provides a method of treating multiple myeloma selected from the group consisting of: superdiploid multiple myeloma and non-hyperploid multiple myeloma, plasma cell tumor, undetermined significance monoclonal γ-globulin disease (monoclonal gammopathy of undetermined significance) ( MGUS) or amyloidosis, the method comprising the administration of a pharmaceutically effective amount of a therapeutically BTK inhibitor, or a pharmaceutically acceptable salt or ester, prodrug , a step of a cocrystal, a solvate or a hydrate.

In one embodiment, the invention provides a method of treating spinal fibrosis selected from the group consisting of primary spinal fibrosis (also known as chronic idiopathic spinal fibrosis) and secondary true red blood Spinal fibrosis of spherocytosis or orthostatic thrombocytosis, the method comprising administering a therapeutically effective amount of a BTK inhibitor or a pharmaceutically acceptable salt or ester, prodrug, co-crystal, solvate or hydrate thereof step. In one embodiment, the invention provides for the treatment of myeloproliferative disorders, myeloproliferative neoplasms, true erythrocytosis, orthostatic thrombocytosis, myelodysplastic syndrome, chronic myelogenous leukemia (eg, BCR-ABL1-positive) ), chronic neutrophilic leukemia or chronic eosinophilic leukemia.

The efficacy of the methods and compositions described herein in treating, preventing, and/or managing an adapted disease or condition can be tested using various animal models known in the art. For example, a model for determining the efficacy of treating pancreatic cancer is described in Herreros-Villanueva et al., World J. Gastroenterol. 2012, 18, 1286-1294. Modes for determining the efficacy of treating breast cancer are described, for example, in Fantozzi, Breast Cancer Res. 2006, 8,212. Modes for determining the efficacy of treating ovarian cancer are described, for example, in Mullany et al., Endocrinology 2012, 153, 1585-92; and Fong et al., J. Ovarian Res. 2009, 2, 12. Modes for determining the efficacy of treating melanoma are described, for example, in Damsky et al., Pigment Cell & Melanoma Res. 2010, 23, 853-859. Modes for determining the efficacy of treating lung cancer are described, for example, in Genes & Development, 2005, 19, 643-664 by Meuwissen et al. Modes for determining the efficacy of treating lung cancer are described, for example, in Kim, Clin. Exp. Otorhinolaryngol. 2009, 2, 55-60; and Sano, Head Neck Oncol. 2009, 1, 32.

Methods of treating inflammatory, immune, and autoimmune diseases, including skin diseases

In some embodiments, the invention provides methods of treating a hyperproliferative disorder in an individual, wherein the hyperproliferative disorder is an inflammatory, immune or autoimmune disorder. In one embodiment, the individual is a mammal. In one embodiment, the individual is a human. In one embodiment, the individual is a mammal, wherein the mammal is a companion animal, such as a canine, feline or equine.

In some embodiments, the invention provides a method of treating an inflammatory, immune or autoimmune disorder in a human comprising a therapeutically effective amount of a pharmaceutically acceptable salt or ester of a BTK inhibitor or a BTK inhibitor, A drug, solvate or hydrate is administered to the human body.

In some embodiments, the invention provides methods of treating an inflammatory, immune or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis Sclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, atopic dermatitis, vesicular pemphigus, eczema and scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular Degeneration, hemangioma, ulcerative colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, postherpetic neuralgia, systemic Labor inlerance, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, suppurative sweat gland inflammation, Sugly's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, Ankylosing spondylitis, asthma, cloning Disease, lupus, lupus nephritis and true red blood cell hyperplasia.

In some embodiments, the invention provides a method of treating an inflammatory, immune or autoimmune disorder, which is a chronic B cell disorder, wherein BCR signaling results in inappropriate autoimmune antibody production or proinflammatory cytokine release and immunity Cells (including inflammatory T cells) are activated. In this type of disease, reducing BCR signaling by inhibiting BTK can result in therapeutic benefit. In some embodiments, the invention provides methods of treating an inflammatory, immune or autoimmune disorder selected from the group consisting of rheumatoid arthritis (RA), juvenile RA, juvenile idiopathic Arthritis, osteoarthritis, psoriatic arthritis, psoriasis vulgaris, pemphigus, vesicular pemphigus, osteoarthritis, infectious arthritis, progressive chronic arthritis, rheumatic polymyalgia , deformed arthritis, traumatic arthritis, gouty arthritis, Wright's syndrome, polychondritis, acute synovitis, ankylosing spondylitis, spondylitis, Shering's syndrome (SS), systemic lupus erythematosus (SLE), discoid lupus erythematosus (disc LE), LE swelling, lupus nephritis (LN), antiphospholipid breakdown, dermatomyositis, polymyositis, autoimmune blood disorders, thrombocytopenia, Idiopathic thrombocytopenic purpura, thrombotic small reduced purpura, autoimmune (cold) lectin disease, autoimmune hemolytic anemia, condensed globulinemia, aplastic anemia, neutropenia Autoimmune vasculitis Behcet's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, scleroderma, systemic sclerosis, myasthenia gravis, multiple sclerosis (MS), chronic local encephalitis, Greene Bally syndrome, chronic fatigue syndrome, systemic labor intolerance, optic neuromyelitis, autoimmune Uveitis, conjunctivitis, keratoconjunctivitis, Graves' disease, thyroid-associated eye disease, chronic thyroiditis, granuloma with microscopic polyangiitis, Wegener's granulomatosis, autoimmune gastritis, autoimmune inflammation Sexual bowel disease, ulcerative colitis, Crohn's disease, graft-versus-host disease, idiopathic steatorrhea, autoimmune hepatitis, active hepatitis (acute and chronic), idiopathic pulmonary fibrosis, bronchitis, Pulmonary interstitial fibrosis, chronic inflammatory disease, sarcoma-like disease, idiopathic membranous nephropathy, IgA nephropathy, glomerulosclerosis, glomerulonephritis (with or without renal disease), pancreatitis and Type I or Type II diabetes.

In some embodiments, the invention provides methods of treating an inflammatory, immune or autoimmune disorder, wherein the inflammatory, immune or autoimmune disorder is a chronic autoimmune and inflammatory disorder, wherein the bone marrow cells and mast cells are BTK signaling causes inappropriate inflammatory cytokine release and immune cells (including inflammatory T cells, autoreactive B cells, activated macrophages, activated mast cells, infiltrating mononuclear cells, and inflammatory cell exudation) Activation and tissue activation of dendritic cell populations. In this type of disease, therapeutic benefit can be reduced by reducing BTK signaling on the surface or intracellular receptors on bone marrow cells. In some embodiments, the invention provides methods of treating an inflammatory, immune or autoimmune disorder selected from the group consisting of diabetic retinopathy, giant cell arteritis, Kawasaki disease, inflammatory bowel disease, Great bowel irritation, idiopathic steatorrhea, bowel disease, postherpetic neuralgia, rheumatic polymyalgia, primary biliary cirrhosis, severe muscle weakness, inflammatory pain, cachexia, teeth Weekly disease, otitis media, pneumoconiosis, mononuclear hematocytosis, emphysema, lung Fibrosis, silicosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease, pulmonary insufficiency, pulmonary fibrosis, pancreatic duodenal resection, benign hyperplasia of the skin (eg psoriasis), myalgia caused by infection, secondary Infected cachexia, systemic labor intolerance, atherosclerosis, granuloma, granuloma with microscopic polyangiitis, suppurative sweat gland inflammation, age-related macular degeneration and amyloidosis.

In some embodiments, the invention provides methods of treating an inflammatory, immune or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis Sclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema and scleroderma), type 1 diabetes, type 2 diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma , ulcerative colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile Idiopathic arthritis, suppurative sweat gland inflammation, Suge's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, lupus nephritis, human leukocyte antigen (HLA) Related diseases, autoantibodies, immunotherapy, Addison's disease, autoimmune endocrine syndrome type 1 (APS-1), autoimmune endocrine syndrome type 2 (APS) -2), Graves' disease, Hashimoto's thyroiditis, multiendocrine autoimmune disease, iatrogenic autoimmune disease, idiopathic parathyroid dysfunction, and leukoplakia.

In some embodiments, the invention provides for treating inflammation A method of sexual, immune or autoimmune disorder, wherein the inflammatory, immune or autoimmune disorder is a dermatological condition in which a signal via BTK media is involved in the recruitment, activation and/or proliferation of inflammatory cells and an inflammatory mediator in the skin. Production of substances and antimicrobial peptides. In some embodiments, the present invention provides a method of treating a skin condition, wherein the skin disease results from a systemic disease in which sensitivity, lymphocyte recruitment, lymphocyte degeneration of cells present by local or lymph node antigens, skin persistence or skin homing Lymphocytic activation, innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans Skin characterization at the cell where the skin disease causes the development of skin lesions. In some embodiments, the invention provides a method of treating a skin disorder selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythrodermic psoriasis, nail sputum, pustular ring psoriasis, pus Pelvic psoriasis, reversal psoriasis, psoriatic arthritis, pussy keratosis, psoriasis, nodular erythema, sweat glands of the hands and feet, atopic dermatitis, atopic eczema, lipid leakage Rash, liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis (LN), lupus erythematosus Lipiditis, erythema multiforme, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, Red spotted pemphigus, nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse skin mast cells Hyperplasia, Red skin disease Hypercytosis, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, Acute moss-like pimples-like pityriasis (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophil dermatitis , cold globulin purpura and hyperglobulinemia purpura.

In some embodiments, the invention provides methods of treating a hyperproliferative disorder, wherein the hyperproliferative disorder is chronic autoimmune and inflammatory conditions of bone, wherein BTK signaling in osteoclasts, mast cells, and bone marrow cells Involved in osteolysis, osteoclast process, bone remodeling process imbalance or bone density loss. Diseases of this type, which also often have autoimmune components, include osteoarthritis, bone loss due to metastasis, osteolytic lesions, osteoporosis, ankylosing spondylitis, vertebral arthritis, diffuse idiopathic hyperosteogeny, Gouty arthritis and bone disorders associated with multiple myeloma. In some embodiments, the invention provides a method of treating a hyperproliferative disorder, wherein the hyperproliferative disorder is selected from the group consisting of osteoarthritis, bone loss due to metastasis, osteolytic lesions, osteoporosis Symptoms, ankylosing spondylitis, vertebral arthritis, diffuse idiopathic hyperosteogeny, gouty arthritis, and bone disorders associated with multiple myeloma.

In some embodiments, the invention provides a method of treating an allergic and atopic disease, wherein an activated B cell produces an IgE antibody and the mast cells are degranulated after Fc ε R conjugation, resulting in release of inflammatory factors and local tissue The response is urgently activated, as well as long-term changes in endothelial cells, neuroreceptors, and other proximal structures that govern the function of organs. These conditions include atopic dermatitis, contact dermatitis, eczema, atopic eczema, pemphigus vulgaris, vesicular pemphigus, nodular pruritus, Stephen-Johnson syndrome, asthma, Airway hypersensitivity, bronchospasm, bronchitis, reactive asthma, chronic obstructive pulmonary disease, type 1 allergic reaction, type 2 allergic reaction, allergic rhinitis, allergic conjunctivitis and other inflammatory or obstructive airways disease. Allergies that can be treated or prevented include, inter alia, allergies to foods, food additives, insect toxicants, dust mites, pollen, animal materials, metals, and certain drugs.

The efficacy of the methods described herein in treating, preventing, and/or managing an adapted disease or condition can be tested using various animal models known in the art. The efficacy of treating, preventing, and/or controlling arthritis (e.g., rheumatoid or psoriatic arthritis) can be assessed using an autoimmune animal model, as described, for example, in Chems Biol. 2010, 17, 123-34 by Williams et al. WO 2009/088986, WO 2009/088880 and WO 2011/008302. The efficacy of treating, preventing, and/or controlling psoriasis can be assessed using a mouse model of gene transfer or gene blockade with target mutations in the epidermis, vascular system, or immune cells, and mice resulting from spontaneous mutations. Models and immunodeficiency mouse models with human skin or immune cell xenografts are all described, for example, in Boehncke et al., Clinics in Dermatology, 2007, 25, 596-605. The efficacy of treating, preventing, and/or managing fibrotic or fibrotic conditions can be assessed using the following pattern: renal fibrosis pattern of unilateral ureteral obstruction, as described, for example, in Kidney International 2009, 75, 1145-1152 by Chevalier et al; Levomycin (bleomycin) induced pulmonary fibrosis pattern, as described, for example, in Moore et al., Am. J. Physiol. Lung. Cell. Mol. Physiol. 2008, 294, L152-L160; various liver/biliary fibrosis modes, description For example, Chuang et al., Clin. Liver Dis. 2008, 12, 333-347 and Omenetti et al., Laboratory Investigation, 2007, 87, 499-514 (mode of bile duct junction); or any of a number of spinal fibrosis mouse models. , such as described in Varicchio et al., Expert Rev. Hematol. 2009, 2(3), 315-334. The efficacy of treating, preventing and/or controlling scleroderma can be assessed using a mouse model induced by repeated local injections of bleomycin as described, for example, by Yamamoto et al., J. Invest. Dermatol. 1999, 112, 456-462. in. The efficacy of treating, preventing, and/or controlling dermatomyositis can be assessed using a model of myositis mice induced by rabbit myosin immunization, as described, for example, in Arthritis & Rheumatism, Phyanagi et al, 2009, 60(10), 3118. -3127. The efficacy of treating, preventing, and/or controlling lupus can be assessed using various animal models, as described, for example, in Ghoreishi et al., Lupus, 2009, 19, 1029-1035; Ohl et al., J. Biomed. Biotechnol., 2011, Article ID. 432595; Xia et al., Rheumatology, 2011, 50, 2187-2196; Pau et al., PLoS ONE, 2012, 7(5), e36761; Mustafa et al., Toxicology, 2011, 290, 156-168; Ichikawa et al. Arthritis & Rheumatism, 2012, 62(2), 493-503; Rankin et al., J. Immunology, 2012, 188, 1656-1667. The efficacy of treating, preventing, and/or controlling Severe's syndrome can be assessed using various mouse patterns, as described, for example, in Chiorini et al., J. Autoimmunity, 2009, 33, 190- 196. The efficacy of treating, preventing, and/or controlling autoimmune hematocytopenia can be assessed using a mouse model induced by intravenous administration of red blood cells and/or platelets from rats, as described, for example, by Exp. Hematol of Musaji et al. .2004, 32, 87-94; or mouse model assessment induced by red blood cells and/or platelets from HLA-matched donor mice, as described, for example, by Bone Marrow Transplant. 1996, 17,985 by Yabe et al. -91.

In one embodiment, the invention provides a method of treating, preventing, and/or managing asthma in a human subject comprising a pharmaceutically acceptable salt or ester, prodrug of a therapeutically effective amount of a BTK inhibitor or a BTK inhibitor The solvate or hydrate is administered to the individual. Asthma puffs as used herein encompasses airway contractions associated with inflammation. Common asthmatic causes include, but are not limited to, exposure to environmental irritants (eg, allergens), cold air, hot air, fragrance, moist air, exercise or exertion, and emotional stress. The invention also provides methods of treating, preventing, and/or managing one or more symptoms associated with asthma. Examples of such symptoms include, but are not limited to, severe cough, airway contraction, and mucus production. The efficacy of treating, preventing, and/or controlling asthma can be assessed using an ovalbumin-induced asthmatic pattern, as described, for example, in Lee et al., J. Allergy Clin. Immunol. 2006, 118, 403-9.

In one embodiment, a method of treating, preventing, and/or managing atopic dermatitis and other atopic diseases in a human subject, comprising pharmaceutically acceptable a therapeutically effective amount of a BTK inhibitor or a BTK inhibitor The salt or ester, prodrug, solvate or hydrate is administered to the individual. Atopic dermatitis as used herein includes atopic skin disease, including Eczema, nodular pruritus, ichthyosis, psoriasis and other skin diseases that constitute persistent or troublesome rashes in adolescents and adults. Atopic skin diseases are often observed in companion animals and are difficult to treat, especially in dogs. Common causes of atopic dermatitis include, but are not limited to, exposure to environmental irritants (eg, allergens), infection (ie, Staphylococcus aureus), mast cell activation, and due to genetic predisposition, dry skin, viral infection, and/or Emotional stress and improper barrier function. The invention also provides methods of treating, preventing, and/or managing one or more symptoms associated with atopic dermatitis. Examples of such symptoms include, but are not limited to, redness, splitting and ichthyosis, pruritus, lichenosis, and epidermal shedding. Pathological thickening of the epidermis and epidermal spine, inflammatory lesions around the subcutaneous blood vessels were acutely observed, and in the chronic case, significant acanthosis and hyperkeratosis were observed microscopically. The efficacy of treating, preventing, and/or controlling atopic dermatitis can be assessed using a skin model induced by dust mite antigen (Dermatophagoides farinae) in Nc/nga mice, as described, for example, by Yamamoto et al. Allergol Int. 2007, 56(2), 139-48.

Method for inhibiting immune response of an organ or cell transplantation

In some embodiments, the invention provides methods of inhibiting an immune response before or after transplantation of an organ or cell in an individual. In one embodiment, the individual is a mammal. In one embodiment, the individual is a human. In one embodiment, the individual is a mammal, wherein the mammal is a companion animal, such as a canine, feline or equine.

In an embodiment, the invention provides a device for a person A method of inhibiting an immune response before or after administration of a cell or a cell comprising administering to the human a therapeutically effective amount of a pharmaceutically acceptable salt or ester, prodrug, solvate or hydrate of a BTK inhibitor or BTK inhibitor individual. In one embodiment, the invention provides a method of inhibiting an immune response prior to or during transplantation of an organ or cell of a human individual, wherein the human individual is a transplant donor comprising inhibiting a therapeutically effective amount of a BTK inhibitor or BTK A pharmaceutically acceptable salt or ester, prodrug, solvate or hydrate of the agent is administered to the individual. In one embodiment, the invention provides a method of inhibiting an immune response before or after transplantation of an organ or cell of a human individual, wherein the human individual is a transplant recipient, the method comprising administering a therapeutically effective amount of a BTK inhibitor or a BTK inhibitor A pharmaceutically acceptable salt or ester, prodrug, solvate or hydrate is administered to the individual. In one embodiment, the invention provides a method of treating a patient having a high level of an anti-allo-HLA antibody with a BTK inhibitor prior to transplantation to reduce anti-allodies that are part of the transplant conditioning treatment - HLA burden. In some embodiments, the invention provides methods of treating a patient having BTK during or after transplantation to reduce regenerated anti-allomeric antibodies. In one embodiment, the invention provides a method of inhibiting allograft rejection prior to, during or after transplantation of a human individual organ or cell comprising medicinally pharmaceutically effective amount of a BTK inhibitor or BTK inhibitor The accepted salt or ester, prodrug, solvate or hydrate is administered to the individual. In one embodiment, the invention provides a method of pre-migrating a conditioning configuration using a BTK inhibitor for a patient undergoing a solid organ transplant. In one embodiment, the invention provides for implantation during, during or after organ transplantation in a human individual (engraftment) A method of inhibiting acute exudation of body fluids by a BTK inhibitor during an early postoperative period, comprising a pharmaceutically acceptable salt or ester, prodrug, solvate of a therapeutically effective amount of a BTK inhibitor or a BTK inhibitor Or a hydrate is administered to the individual. In one embodiment, the invention provides a method of inhibiting infiltration of bone marrow cells into allograft tissue by BTK inhibition prior to, during, or after organ transplantation. In one embodiment, the invention provides a method of reducing physiological changes associated with ischemia/reperfusion in an organ after transplantation and thereby reducing the pro-inflammatory signal leading to leukocyte migration. In one embodiment, the invention provides a method of inhibiting the presentation of potent B cell antigens to T lymphocytes during the post-implantation phase of organ transplantation and thereby reducing allograft-specific cytotoxicity and development of T helper cell populations Including CD8 T cells, Th1 T cells, Th2 T cells and Th17 T cells and other pro-inflammatory T cell populations. In one embodiment, the invention provides a method of preventing B cell reactivation following transplantation to prevent treatment by a BTK inhibitor at a dose of BCR signaling in a chamber described in a transplanted organ. In one embodiment, the invention provides a method of preventing B cell reactivation after transplantation, which is to prevent treatment by a BTK inhibitor at a dose of BCR signaling in a chamber that is efflux from the transplanted organ to the lymph node. In one embodiment, the invention provides a method of treating acute or chronic graft rejection following organ transplantation to prevent BTK inhibition by a dose of BCR signaling in a chamber as described in an inflamed tissue within a transplanted organ Treatment. In any of the foregoing embodiments, the organ or cell transplantation is selected from the group consisting of heart transplantation, kidney transplantation, kidney transplantation, lung transplantation, liver transplantation, ABO incompatible transplantation and stem cell transplantation. In some embodiments, the invention provides a method of treating a human subject, wherein the human individual is a transplant recipient, the method comprising the step of administering a BTK inhibitor.

In one embodiment, the invention provides a method of treating a human subject, wherein the human body is a transplant recipient, the method comprising the step of administering a combination of a BTK inhibitor and a treatment selected from the group consisting of corticosteroids , rituximab, cyclosporine, motefil mycophenylate, cyclophosphamide, belimumab, other immunosuppressive drugs, and combinations thereof. In one embodiment, the invention provides a method of treating a mammal, wherein the mammal is a transplant recipient, the method comprising the step of administering a combination of a BTK inhibitor and a treatment selected from the group consisting of: Corticosteroids, rituximab, cyclosporine, mycophenolate mofetil, cyclophosphamide, belimizumab, other immunosuppressive drugs, and combinations thereof. In one embodiment, the administration of the BTK inhibitor is reduced by a dose selected from the group consisting of corticosteroids, rituximab, cyclosporine, mycophenolate mofetil, cyclophosphamide , belizumab, other immunosuppressive drugs and combinations thereof. In any of the foregoing embodiments, the human is an adult. In any of the foregoing embodiments, the human is a pediatric patient.

In one embodiment, the invention provides a method of treating graft versus host disease (GVHD) comprising the step of administering a BTK inhibitor, wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation GVHD associated with bone marrow transplantation, thymus GVHD, skin GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and slow Sexual GVHD.

Example Example 1. Phase 1, single-center, non-blind, single treatment study

The first phase, single-center, non-blind, single-treatment study was conducted in healthy volunteers to assess BTK occupancy after administration of multiple doses to healthy adult individuals in the fasted state of Formula (II). The study focused primarily on measuring the BTK footprint in peripheral blood mononuclear cells (PBMC) by formula (II) and measuring lymphoid B during and after multiple oral doses of 15 mg per day in healthy individuals. The pharmacodynamics (PD) of formula (II) was characterized by activating the expression of markers, CD69 and CD86. This study evaluated pharmacokinetic (PK) profiles, safety and tolerability after administration of multiple doses of formula (II) in healthy individuals as a secondary goal. Moreover, this study measures the effect of formula (II) on peripheral blood T cells and bone marrow-derived suppressor cells (MDSC).

The study recruited 40 healthy and female adults who did not smoke. A dose of 15 mg of the formula (II) (1 x 15 mg capsules) was administered to each body once daily (QD) for 7 consecutive days (Day 1 to Day 7) with a washout period (6 days). PD blood samples from each body were collected before dosing on day 1, throughout the study period, and up to 144 hours after dosing on day 7, to characterize the PD effect of formula (II). PK samples of formula (II) were also collected before dosing on day 1, throughout the study period, and 24 hours after dosing on day 7. In addition, potential (II) safety issues are monitored through physical examination, vital sign measurements, 12-lead electrocardiogram (ECG), AE, and clinical laboratory testing.

The BTK occupying line of formula (II) was measured in PBMC by means of a biotinylated variant (II) analog probe. The effect of formula (II) on functional activation of B cells (measured by phosphorylation of BTK and up-regulation of CD69 and CD86 activation markers) was also assessed after BCR stimulation.

The mean measured plasma concentration of formula (II) versus time data (PK data) and the average BTK occupancy of formula (II) (PD data) were fitted with the PK and PD patterns of the biological period of the chamber, which can predict different doses and dose configurations, respectively. And PK and PD during the duration of the dose. The biological period PK mode for fitting the chamber of the concentration (II) concentration versus time data is depicted in Figure 1 (A). The mode is a two-compartment PK mode with simple average data of oral absorption at a delay of d (1, 3). The fitting (optimization) is done via a weighted least squares method. Room q1 represents the primary room (ie blood or circulatory system), room q2 represents the drug delivery point (ie the general intestine, stomach and / or duodenum), and room q4 represents the surrounding room, rate k (3, 2), k (4,1) and k(1,4) represent the inter-chamber rate, the rate k(0,1) represents the output rate (ie the clearance of formula (II)), and s1 represents the sampling point (ie blood or circulatory system) ).

After 15 mg of the formula (II) dose on day 1, the pattern fits the average PK concentration observed on day 1 (Fig. 1 (B)). Figure 1 (C) shows the fit of the same pattern, with the PK concentration data for Day 7 plus the parameters fixed from Day 1. The Day 1 pattern fit visually illustrates the average PK data for Day 7. Therefore, after repeated QD administration, the PK on day 1 was similar to the PK on day 7, with no significant accumulation.

Figure 2 illustrates the biological period BTK transfer PD mode for fitting the chamber of the BTK occupying data of formula (II), wherein the q7 chamber represents unmodified BTK (i.e., BTK not covalently bound to formula (II)), q6 chamber represents covalently bound to BTK of formula (II), and each chamber has a shift rate (input rate - output rate). Assume that the output rate k(0,7) is equal to k(0,6). The rate constant k(6,7) is the saturable rate constant, which represents the irreversible BTK deactivation of formula (II). Occupancy of the active site of BTK kinase was determined by the ratio: q6/(q6+q7). Symbol s2 represents the sampling point (i.e., the central chamber or blood). This same mode is allowed to be re-operated at different sampling points (i.e., q4, possibly representing bone marrow, lymph nodes, or other tissue chambers of interest, having a different BTK resynthesis rate than the central chamber).

The PK/PD mode is linked to the model described in Figure 1 (A) and Figure 2 and is predicted from the human body sample treated with the BTK covalent inhibitor of formula (II) based on empirically determined BTK resynthesis rate in the central compartment. The BTK target is occupied. In addition to the target cell movement between the surrounding and central chambers, the flux of the unmodified (new) BTK target binding site to the central compartment is also reflected in the re-synthesis of BTK in the target cells and the newly produced content. BTK of target cells.

Figure 3 illustrates the final pattern fit (shown as data points) for the average percentage of BTK occupation data obtained during healthy volunteer studies. During mode development, when compared to the rate of BTK resynthesis after subsequent full occupancy dose, the BTK resynthesis rate was found to be higher after the initial dose administration, which resulted in a lower percentage of BTK target occupancy. For example, during Day 1 and Day 2 of the 15 mg repeated dose study, the BTK target occupied approximately 60% at the end of the dosing interval and the half-life of the occupied BTK was estimated to be ~20 hours (Figure 3). .

Repeated oral administration of 15 mg of the formula (II) QD dose unexpectedly resulted in a high and sustained steady state BTK occupancy. After discontinuation of dosing in the steady state, the half-life of the occupied BTK (i.e., the time required to reduce the BTK occupancy to the initial value of 50% via BTK resynthesis) was estimated to be ~119 hours. The final mode is adapted to the rate of change over time by stepping on the BTK resynthesis rate constants on Days 1 and 2 to a lower fixed value on Day 3 and subsequent days. Data from this study was found to lead the formula (II) treatment of healthy volunteers resynthesis occurs BTK rate changes with time, of from 20 hours to 119 hours, t _1/2 t _1/2, resulting in a steady state after reaching The slower BTK target occupies a recession (Figure 3). Due to changes in the rate of BTK resynthesis, an early artificial fit of the 15 mg period showed that the steady state data could not fit properly with the initial mode parameters and vice versa (Figures 4A and 4B).

The pattern had the potential to fit phospho-BTK data from healthy volunteers treated with 15 mg of Formula (II) QD for 7 days, as exemplified in Figure 5. The peripheral blood B cell line was sampled at the indicated time and stimulated in vitro with an anti-IgM antibody to activate BCR signaling via BTK. The phosphorylation status of BTK was assessed by phospho-flow cytometry and expressed as a percentage of control (pre-study) samples.

Although the t1/2 of the pharmacodynamic markers of BTK inhibition administered by formula (II) and the BTK target vary over time, the pharmacokinetic plasma concentration in plasma is not repeated for the time profile. change. This is consistent with the pharmacokinetic half-life of formula (II) being shorter than the half-life of the dose interval. Figures 6A and 6B show that the 15 mg PK mode accurately The pharmacokinetic profiles of 40 healthy volunteers were predicted to be administered by oral doses of 25 mg (II) on day 1 and again on day 7, indicating that the pattern predicts exposure to different doses of the drug and that exposure is not daily. change. Conversely, the rate of rapid BTK resynthesis observed after the initial 25 mg dose was lower than when the second dose was given one week later (Figures 7A, 7B, and 7C). The PD parameter from the first dose of the 15 mg test fits the occupancy data for the first 25 mg dose. Surprisingly, the PD parameter from the 7th consecutive 15 mg dose must fit the second 25 mg dose given one week after the first dose. These unexpected data and the increased occupancy in the first 15 mg dose studies indicate a long-lived effect of a single dose of Formula II on BTK resynthesis, which confirms the cumulative BTK occupancy in multiple dose configurations.

In the healthy volunteer study of formula (II), when the initial dose reached the higher BTK target occupancy level, repeated observations were observed in the chamber consisting of normal peripheral blood B cells. This phenomenon of the trend of slower BTK resynthesis rate. This finding leads to the development of a PK/PD pattern that accurately predicts the BTK target occupancy value across the entire dose group and provides a means to predict the effect of BTK resynthesis rate on the bioavailability of a particular drug delivery configuration, as shown in Figure 8. As illustrated in Figure 19.

PD mode was used to simulate the performance of a 15 mg (II) BID dosing configuration compared to a 30 mg QD dosing configuration. The results shown in Figure 8 illustrate the superior occupancy achieved by using a lower dose of a 15 mg BID dosing configuration. Using a low dose of formula (II) may unexpectedly occupy a steady state of about 95% or greater because it is relatively low in healthy volunteers. BTK resynthesis rate.

The PD mode was used to simulate the performance of the 15, 30, and 45 mg Formula (II) QD dosing configurations, as illustrated in Figure 9, and to simulate the performance of the 15, 30, and 45 mg Formula (II) BID dosing configurations, as shown in Figure 10. Illustrated in the middle. BTK inhibition compared to 30 mg QD was simulated in a healthy volunteer with a 15 mg BID dose (Figure 11) as measured by pBTK values in normal peripheral blood B lymphocytes after ex vivo stimulation of BCR.

In healthy volunteers with 15 mg and 25 mg of formula (II), PK performed very well after repeated dosing, with little to no PK accumulation or change. When the pattern fits 25 mg PK data, the model PK parameter estimates based on the 15 mg PK data did not change substantially (Figures 7A, 7B, and 7C). However, the PK pattern based on these lower doses did not scale well to the 50 mg PK data obtained from healthy volunteers in the dose escalation study unless the k(4,1) rate constant was lowered (Figure 12). ).

The rate of BTK resynthesis varies with disease and disease burden and is different from BTK in normal tissues of healthy volunteers. Therefore, the PK/PD mode was used in Figures 13 to 16 to estimate the higher steady state BTK occupancy of the dose of formula (II) (ie, the oncology dose), which was adjusted to fit the higher dose of PK data. k(4,1). The average patient data was overlaid on the simulated BTK target footprint, showing a good steady state pattern, close to the average occupancy data obtained with 100 mg QD, 100 mg BID, 250 mg QD, and 400 mg QD dose. The data is limited by the average occupancy estimates of the sparse two points obtained in the clinical study. The opposite of the multi-day washout data obtained with lower doses in healthy volunteers. However, the estimates provide additional support for the performance of the PK/PD mode.

Figures 17 to 20 show simulation results predicting the administration of BTK targets for two weeks of administration of formula (II) with different administration strategies. The PK/PD mode was used to predict BTK occupancy for 2 weeks of administration in different dose configurations (Figures 17-20). Figure 17 compares the 30 mg QD with a 15 mg BID dose configuration. Figure 18 shows a 60 mg BID loading dose followed by a 30 mg QD maintenance dose after one week. Figure 19 shows a 60 mg BID loading dose followed by a 15 mg QD maintenance dose after one week, and Figure 20 shows a 60 mg BID loading dose followed by a 7.5 mg QD maintenance dose after one week. Such administration configurations are examples of strategies that may be used to control BTK-mediated disease states in which BTK resynthesis values are altered during acute and chronic forms of disease, with disease control, or during disease modification processes.

Figure 21 illustrates the pattern fit for the 7-day BTK target occupancy from healthy human volunteers after oral administration of 15 mg of formula (II) QD, demonstrating >90% at this low dose after re-synthesis rate decline It is occupied by a steady state spike.

Figure 22 illustrates the unexpected finding that the average intracellular BTK protein content after the initial dose was initially increased during treatment of healthy human volunteers with formula (II) as measured by flow cytometry. When the rate of patterning BTK resynthesis was found to decrease, then the intracellular BTK protein content was clearly found to decrease at the same critical time (between day 2 and day 3). The effect of formula (II) on the rate of BTK resynthesis in healthy human volunteers is Two orthogonal methods (ie, flow cytometry and BTK target combined with PK patterning occupy the ELISA) confirm important novel findings. The trend of BTK resynthesis rate similar to the dose response (rather than time response) phenomenon was found after administration of healthy human volunteers in a single day of QD and BID dose range, as exemplified in FIG.

As exemplified in Figures 24A, 24B, 24C, 24D, 24E, and 24F, the link between exposure and response can be estimated by the Emax curve that estimates the pharmacodynamic effect of the plasma concentration given by the active agent. Description. Pharmacodynamic data from healthy volunteers administered in a single dose of 50, 75 or 100 mg of formula (II) or 2.5, 5, 25 or 50 mg of formula (II) are presented. The data were obtained from samples taken 12 hours into the washout period and represent the integrated BTK resynthesis rate and functional recovery in individual dose groups. These results did not predict that the repeated low dose formula (II) substantially increased the ability of the BTK target to occupy and provide further inhibition of downstream PD markers for BCR signaling, as observed with a dose of 15 mg QD for 7 days.

PBT/PD mode was used to simulate pBTK inhibition using a 15 mg (II) BID and 30 mg (II) QD dosing configuration (Figure 11). The pBTK inhibition configured in BID was 92% or greater. The BTK resynthesis rate from the end of the treatment interval and the functional recovery of BCR-stimulated BTK and downstream markers (such as CD69 up-regulation, CD86 up-regulation, and CXCR4 down-regulation) are shown in FIG. Between the percentage of BTK occupancy/inhibition and the functional recovery of the selected downstream PD marker may be due to the compensatory signaling pathway activated by in vitro BCR stimulation in normal B cells. difference.

Due to the feedback loop in the BTK pathway, it is necessary to adjust the rate of BTK resynthesis in PD mode, where partial inhibition of BTK stimulates an increase in BTK resynthesis rate and stronger inhibition results in a decrease in BTK resynthesis rate. BTK targets that meet the requirements for resynthesis in tissue chambers of therapeutic interest and/or in tissue chambers with the fastest BTK resynthesis rate must accumulate and therefore must overcome the compensation mechanism. Although it has been reported that mRNA expression is induced by the NFkB signaling pathway, the discovery that BTK modulation in humans is caused by low-dose (II) treatment is a novel finding, as previously reported. This finding is provided in combination with the development of a PK/PD patterning tool that effectively demonstrates the exposure-response relationship of BTK covalent inhibitors, including long-lasting effects on BTK and BCR pathways after reducing plasma (II) levels. A unique and novel method for identifying effective low dose configurations for the treatment of autoimmune disorders, allergic and atopic diseases, inflammation, and other chronic diseases that are responsive to selective BTK inhibition is identified.

In summary, the results of healthy volunteer studies are as follows. The PK/PD pattern was developed based on low doses in healthy volunteers and adjusted to fit higher dose data based on PK data from tumor patients. The PK of formula (II) performed very well after repeated administration with little to no accumulation or alteration of PK. PK mode parameters were estimated based on a reasonable moderate extension of 15 mg PK data to 25 mg PK. It is necessary to adjust the rate constant between the central and surrounding chambers to simulate the higher doses used in oncology. PK. In PD mode, the rate of BTK resynthesis was observed to change over time after a single dose of formula (II). This may reflect changes in parameters such as lymphocyte migration between chambers (ie, from the surrounding chamber to the central chamber with a faster rate of BTK resynthesis) and increased rates of BTK protein synthesis. The total BTK line of each cell in the central chamber increases after the dose that results in the incomplete BTK target and decreases after the dose that results in the complete BTK target, with BTK involving BTK or controlling the rate of BTK resynthesis The feedback loop of the downstream members of the communication route is consistent. The modeled BTK resynthesis rate (t _1/2 = 119 hours) appeared to fit data from volunteers who were healthy after 7 days of administration of 15 mg of formula (II) and 25 mg of formula (II) of BID. An early 15 mg QD dose or a single 25 mg QD dose also had a faster rate of BTK resynthesis (t _1/2 = 20 hours).

In healthy volunteers, BID administration increased to >90% after 2 weeks of repeated administration of 15 mg. Similar results were obtained with pBTK. Visual inspection of the modeled data indicates that BTK, which reaches an approximately steady state, is occupied by approximately 8-9 days. However, the time to reach the apparent steady state occupied by high BTK decreases with higher dose values. A high average BTK occupancy was quickly achieved with a loading dose/maintenance dose configuration and then an average BTK occupancy of >90% was achieved at the C _valley with a lower formula (II) BID dose.

Example 2. Comparison of oral administration of QD infusion and oral administration of low-dose continuous PO in rats with formula (II): pharmacokinetic profile and BTK target occupancy

In order to evaluate the effect of continuous low-dose administration on oral administration of formula (II), 6 male rats in each group were administered orally by oral administration. A dose of grams per kilogram per day or formula (II) is treated for 14 days. Six male rats per group were treated with formula (II) at a concentration of 100 and 500 ppm in the diet; the control group (no vehicle, no feed) was included in the study. All animals were evaluated for pharmacokinetics on day 14 during the nighttime cycle adapted to the diet group. Spleens were harvested at the time of dissection and spleen cells were harvested and chilled for BTK target occupancy analysis. The inactivated BTK line present in normal spleen cells was measured using an BTK active site specific probe in an ELISA assay. Plasma concentrations of formula (II) were measured using liquid chromatography/mass spectrometry; pharmacokinetic parameters were assessed using WinNonlin (Pharsight, Cetara).

Formula (II) was rapidly absorbed in the oral feeding treatment group and had a relatively high Cmax (506 ng/ml) when compared to the AUC0-12 value (864 ng ̇h/ml). Conversely, rats treated with dietary formulations have a relatively flat concentration versus time profile and extended exposure throughout the feeding cycle, with a Cmax value The 1/10th AUC0-18 value is exemplified in Figures 26A, 26B, 26C, 26D and 26E. In these unstimulated rats, there is clear evidence for the activity of formula (II) in the tissue chamber of interest, since the spleen cells from the diet group clearly have a similar tube feeding profile from 30 mg/kg/day. The BTK target of spleen cells is occupied. This strongly supports the delivery of small or pulsed doses of extended release PO formulations or controlled release PO formulations to extend the low dose of formula (II). Targeting can achieve therapeutic levels in diseased tissue, only The dose is sufficient to cope with the rate of BTK synthesis therein.

Example 3. Recovery of BCR function after BTK in mice treated with formula (II) to inhibit in vivo mode

Stimulation by B cells via B cell receptor (BCR) with antibodies (eg, anti-IgM) results in BTK activation and subsequent cellular changes, including upregulation of various cell surface receptors. The inhibition of BCR-induced protein phosphorylation inhibition downstream of Btk and the upregulation of surface receptors provide a means to assess the activity of Btk inhibitors. In the first study, BTK target occupancy over time in spleen cells was measured, providing evidence of BTK resynthesis in the tissue chamber of interest.

A team containing 25 mice was administered at a single oral dose of 25 mg/kg of ibrutinib, CC-292 (formula (XVII)) or formula (II), respectively. Mice were sacrificed at 3, 6, 12, 18 and 24 hours after treatment with BTK inhibitors (Figures 27A, 27B and 27C). Spleen cell preparations for spleen and prepared for flow cytometry were analyzed to analyze B cell function. Fresh or chilled spleen cells were cultured with α-IgM to stimulate BCR, and up-regulation of CD69 (early functional marker of B cell activation) was analyzed by flow cytometry.

As shown in Figures 27A, 27B and 27C, Formula (II) and Ibubinib showed almost complete inhibition of the in vitro anti-IgM-induced response in B cells 3 hours after dose, partially inhibiting CD86 for 24 hours and CD69 performance. In contrast, incomplete inhibition was observed at 3 hours with formula (XVII) (CC-292), consistent with the incomplete BTK target occupancy of formula (XVII). The CD86 inhibition % of formula (II), ibupotinib and formula (XVII) (CC-292) were 67.9%, 62.9% and 28.1%, and the % inhibition of CD69 were 84.3%, 83.4%, and 44.8%, respectively.

This study also monitored the downstream marker S6 phosphorylation of BTK activity. The three BTK inhibitors simultaneously inhibited basal state and anti-IgM-induced S6 phosphorylation and showed the same activity level (Formula (II) > Ibubinib > Formula (XVII)), as exemplified in Figures 28A and 28B. In a second study, the effects of another BTK inhibitor (XXI) and formula (II), which inactivate the kinase covalently, were compared to assess BCR function recovery and B cell activation, as shown in Figures 29A and 29B. As illustrated.

Evaluation of BTK target occupancy in splenocytes from mice demonstrates that the BTK resynthesis rate in the group treated with the BTK covalent inhibitor is higher than the BTK in the group treated with the formula (XVII) (CC-292). The synthesis rate is slower. This represents an additional element of BTK target resynthesis in the tissue compartment (spleen) comprising (1) BTK protein released by reversing the binding of formula (XVII) and (2) in which BTK signal transduction is only subject to Increased rate of BTK resynthesis in partially inhibited splenocytes. Comparison of BTK resynthesis assays in individual individuals treated with formula (II) showed that spleen cells from treated mice recombined at a faster rate after a single oral dose than observed in human B cells. .

Example 4. Evaluation of BTK target occupancy in peripheral blood and lymph node lymphoma lesions in dogs with spontaneous lymphoma after treatment with formula (II)

Dogs were orally administered with formula (II) once a day and evaluated every 14 days for every 7 days and after the first 4 weeks of the study. On day 0 PBMCs and lymph node fine needle extracts (lymphoma patients only) for PD analysis were obtained at 0 hours and 3 hours and before the 7th day of drug administration (Cmin). In each team, PK analysis was performed on a study consisting of blood samples taken at 0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after drug administration on day 14 of 2 dogs.

Peripheral blood mononuclear cells (PBMC) were isolated from the blood and were positively magnetically enriched for CD21+ B cells. For fine needle extraction (FNA) samples, red blood cells were dissolved in ammonium chloride dissolution buffer. Purified peripheral B cells and FNA samples were snap frozen for measurement of BTK target occupancy. The BTK target occupancy was measured by ELISA using anti-BTK as a capture antibody and a biotinylated active site probe for BTK, followed by streptavidin-HRP as a detection reagent. Baseline signals for each sample were provided by in vitro incubation of formula (II). The BTK occupying line in B cell lysates from peripheral B cells and lymph node FNA preparations was calculated as a percentage of control after baseline chemiluminescence correction. All samples were repeated four times.

Complete BTK occupancy (defined as occupancy) occurred in surrounding B cells in all groups 3 hours after administration 90% of BTK). Complete BTK occupancy was also observed in peripheral blood samples before the steady-day 7th day dose (24 hours after dose administration [QD team] or 12 hours [BID team]). The 5 mg/kg QD team was excluded from the analysis due to sample quality and FNA samples were not obtained from the 2.5 mg/kg QD team. Complete BTK occupancy was observed in all teamed lymph node FNAs 3 hours after administration ( 90%). In all measured cohorts, BTK occupancy in lymph node FNA was more than in the peripheral blood sample before the dose on day 7 of treatment (24 hours after dose administration (QD team) or 12 hours (BID team)). low.

Figure 30 shows that matched samples of peripheral blood mononuclear cells and FNA from tumor-bearing lymph nodes after administration of formula (II) showed complete BTK occupancy in blood and lymph nodes 3 hours after dose. However, in the tumor-carrying lymph node compartment, the target occupancy was lower than that observed in the peripheral blood at the time point before the 7th day dose. This is consistent with a higher rate of BTK resynthesis in the proliferative tumor room than in normal B lymphocytes sampled in the central (peripheral blood) chamber. Although high occupancy (82-88%) was observed in lymph nodes bearing tumors, a faster rate of resynthesis compared to peripheral blood indicates a shorter half-life.

Example 5. Dose response of BTK target after treatment with formula (II) in relapsed and recalcitrant CLL patients and its effect on intracellular BTK total protein expression

High-level BTK target occupancy established and maintained during dose escalation trials in individuals with relapsed/refractory CLL is based on higher doses from 100 to 400 mg QD or 100 to 200 mg BID (II) ) Previous administration. Figure 26 shows the results of BTK target occupancy in the first 28 days of treatment in the selected dose group. Evaluation of circulating tumor cells in the peripheral blood chamber demonstrates that a total daily dose of more than 200 mg delivered at a once-daily or twice-daily dosing schedule results in complete (>90%) BTK targets throughout the dosing interval of CLL patients. occupy. However, a higher percentage of BTK occupancy was observed in individuals dosed with 100 mg BID than any QD dosing schedule. Use a daily dose of up to 400 mg Assessment of BTK occupancy demonstrates that rapid conversion to fully occupied BTK occurs during the absorption and initial elimination phase of the pharmacokinetic concentration-time profile. In all treated individuals, samples taken from the peripheral blood chamber 3-4 hours after dose showed complete BTK occupancy, although it was maintained at a reduced plasma concentration of formula (II). BTK resynthesis was significantly faster after 100 mg of formula (II) QD administration than after 100 mg BID administration, as exemplified in Figure 31.

The sharp peaks of Tmax and plasma concentrations that occur rapidly after oral administration of formula (II) for 1 hour are sufficient to saturate the BTK site, while covalent interactions at the kinase target site result in targets in this patient population. Occupy extension. Penetration into the tissue compartment (such as bone marrow, spleen, and tumor-affected lymph nodes) is evidenced by the presence and increase of CLL lymphocytosis in the peripheral blood chamber, which was obtained during the first week of dosing. Both blood samples and PBMC samples used to assess the occupancy of the BTK target were confirmed. In this instruction, rapid BTK resynthesis in tumor cells in the CLL cell compartment is observed at a steep rate of decline in the percentage of BTK sites occupied by formula (II), which is in normal peripheral blood cells in healthy volunteers. The observed rate is compared (compare the linear slope estimates of Figures 25 and 34).

Figure 14 demonstrates that using the modified PK/PD mode described above, a good fit of the BTK occupancy data for repeated doses of Formula (II) has a slower k(4,1) rate than using a lower dose. This rate reflects the saturable elements that penetrate into the surrounding chamber and may involve the elimination of the target medium.

In CLL patients, BTK targets account for a decrease in BTK activation following in vitro BCR stimulation, as exemplified in FIG. We also It was unexpectedly noted that treatment with formula (II) caused a decrease in cellular BTK levels in CLL tumor cells sampled after reaching full BTK target occupancy. This finding demonstrates that the rate of BTK resynthesis in B cells can be altered as described in formula (II) in healthy volunteers (i.e., normal B cells). The higher rate of BTK resynthesis in cancer patients and related tissue compartments of patients with systemic immune or inflammatory conditions can be addressed by adjusting the administration strategy for the chamber of interest.

Example 6. BTK Inhibitory Effect on Solid Tumor Microenvironment in Ovarian Cancer Model

The therapeutic efficacy of the BTK inhibitor of formula (II) was studied by treatment of the solid tumor microenvironment using the ID8 and primordial ovarian cancer murine model. The human ovarian cancer model (which includes the ID8 and primordial ovarian cancer model) and other animal models are described in Fong and Kakar, J. Ovarian Res. 2009, 2, 12; Greenaway et al., Gynecol. Oncol. 2008, 108, 385- 94; Urzua et al., Tumour Biol. 2005, 26, 236-44; Janat-Amsbury et al., Anticancer Res. 2006, 26, 3223-28; Janat-Amsbury et al., Anticancer Res. 2006, 26, 2785-89. Animals were treated with oral administration of 15 mg vehicle or formula (II) / kg / BID. The results of the study are shown in FIGS. 35A, 35B, 36, 37, 38A, 38B, 39A, and 39B.

Figure 35A and Figure 35B demonstrate that BTK inhibitor of formula (II) depletes ID8 ovarian cancer growth in the ID8 homologous source murine model. Figure 36 shows that tumor response treated with a BTK inhibitor of formula (II) in tumor-bearing mice correlates with significantly reduced immunosuppressive tumor-associated lymphocytes. Figure 37 shows the treatment depletion of BTK inhibitors of formula (II) in ID8 ovarian cancer growth in the same base-source murine model (by reduced tumor volume). Figure 38 shows that tumor response induced by treatment with a BTK inhibitor of formula (II) in tumor-bearing mice correlates with significantly reduced immunosuppressive B cells. Figure 39 shows that tumor response induced by treatment with a BTK inhibitor of formula (II) correlates with significantly reduced immunosuppressive tumor-associated Tregs and increased CD8 ⁺ T cells.

The results shown in Figures 35-39 illustrate that the BTK inhibitor of formula (II) modulates the unexpected efficacy of the tumor microenvironment in predicting a mode of efficacy in treating human ovarian cancer.

Example 7. Effect of sub-long-term low-dose administration of formula (II) on the development of T cell-dependent antibody response (TDAR) in male and female rats

Rats were orally administered with a dose of 1, 2.5 and 5 mg/kg/day of vehicle or formula (II) for 91 days. The development of T cell-dependent antibody response (TDAR) was assessed in 16 rats per sex, and was immunized on the 50th day with subcutaneously injected keyhole limpet hemocyanin (KLH). Continued dosing and blood samples were taken via the sublingual vein on days 57, 64 and 71 into tubes without anticoagulant and allowed to agglomerate at room temperature for at least 30 minutes, then the serum was divided into 4 approximately the same Aliquots were taken and stored frozen at approximately -60 to -90 °C. Anti-KLH IgM and IgG antibody values were determined using an enzyme-linked immunosorbent assay (ELISA). 41A, 41B, 41C, 41D, 41E, 41F, 42A, and 42B, Figure 42C, Figure 42D, Figure 42E, and Figure 42F illustrate the trend of anti-KLH antibody responses in male and female rats.

Surprisingly, even these low doses had a significant effect on the intensity of IgM and IgG produced by the reaction of foreign antigens (using the untransformed data for the Kruskal-Wallis test at each time post-immunization; GraphPad Prism). The dose range tested in this rat mode is equal to the human dose of 10, 24 and 48 mg QD. This result is consistent with the findings presented in Example 1, which shows that a low daily dose of formula (II) can accumulate BTK target occupancy over time and reach a steady state BTK in the tissue chamber of interest (in this case, the lymph node) Inhibition, committed to the desired physiological changes. The use of selective BTK covalent inhibitors in chronic autoimmune and allergic disease indications to specifically reduce TDAR response, no opposite immunosuppression or loss of host resistance.

Example 8. Effect of Formula (II) on Osteoclast Bone Lesions in a Rat Model of Tumor Bone Metastasis

Rats were inoculated with MDA-MB-231 tumor cells on day 1, baseline radiographs were taken on day 2 and treatment with formula (II) was started on day 8. Radiographs were taken on days 10, 17, 24, 31, 38 and 41. The anti-lytic activity was determined by the difference in bone mineral density and visual lysis score between the drug-treated and vehicle-treated groups on each observation day, and also in the left tibia inoculated with tumor at baseline (Day 2). Bone density and visual dissolution scores were determined as compared to days 10, 17, 24, 31, 38 and 41.

The activity of formula (II) is based on quantitative assessment of bone density changes The measurements are as illustrated in Figures 40A, 40B, 40C, 40D, 40E, 40F, and 40G and are based on a semi-quantitative visual score of osteolytic lesions on a digital image of the tibia radiograph. Radiographs were used blindly for both analyses. The uninoculated and untreated simple group (Group 6, n=3) had a baseline mean left tibia density of 195.7 ± 1.7, which increased statistically significantly to 203.6 ± 1.7 on day 41. A comparable change was observed with the right tibia of this group. No visual osteolysis was detected in any of the rats in the simple group. The average bone density of 4% increased from baseline to end of study is presumably reflecting the normal growth of these rats.

The vehicle control group had a baseline mean density of 206.2 ± 1.7, which decreased statistically significantly from 11% to the lowest point of 183.4 ± 1.7 on day 31, but increased slightly to 192.0 ± 1.7 on day 41 and relative to baseline ( Day 2) is equivalent to a non-significant decrease of 7%. From day 31 to day 41, the control group had an average visual dissolution score of 2.3, reflecting an average moderate to severe osteolysis. Osteopathic lesions were seen in 6/6 of the control groups from day 24 to day 41. Although radiograph data for all observation days are evaluated, the overall results in this model are usually based on the observed changes observed in the final measurement. However, the bone mineral density and visual lysis results of the control group discussed above indicate that the data for Day 31 is more robust than the data for Day 41. Considering the apparent tumor rejection on day 41, consider the treatment outcomes for both days 31 and 41 of groups 2-5.

The zoledronate group (Group 2) gave the expected anti-osteolytic activity in this mode. The average left tibia density increased from 200.0±1.6 on the 2nd day to 207.8±1.6 on the 31st day and 211.2±1.6 on the 41st day. 4-6% was added and was significantly greater on these days compared to the first control group. The mean visual dissolution scores on Days 31 and 41 were 0.7, respectively, reflecting an average of no dissolution to minimal dissolution.

Rats treated with 3 and 30 mg of formula (II)/kg (Groups 3 and 4, respectively) obtained bone mineral density and visual lysis results similar to those of the vehicle control group. The left tibia bone mineral density was not significantly different from the vehicle control group in the 3 or 30 mg/kg group on any observation day, and the 30 mg formula (II)/kg group on day 24 was excluded, compared to the first group. A density that causes a significant drop. On Days 31 and 41, the average visual dissolution scores of 3 and 30 mg/kg ranged from 2.2 to 3.0, reflecting an average moderate to severe osteolysis. In Group 3, 1 animal did not have an intuitive osteolytic lesion, but all other rats in Groups 3 and 4 had a sharply increased visual score.

Rats treated with 180 mg of formula (II) QD/90 mg of formula (II) BID/kg (Group 5) showed slightly varying bone density and visual lysis from day 2-41. The average left tibia density decreased from 1-2% on day 2 from 201.4±0.6 to 199.1±0.6 on day 31 and 197.2±0.6 on day 41, respectively. On day 31, but not on day 41, the density of left tibia in group 5 was significantly greater than in the first control group. On Days 31 and 41, the mean visual lysis scores for Group 5 were 1.2 and 1.5, respectively, reflecting the average lowest to moderate osteolysis. In this group, 2 rats never developed an intuitive left tibia lesion and 3 rats had no visual lesions on days 31 and 41.

This study has novel results in two ways. First, the knot It was shown to be active against the osteoclast process in vivo in a tolerable dose of formula (II) in the relevant tissue chamber of nu/nu rats, showing activity downstream of BTK for RANKL and other bone marrow effectors. Second, the Group 5 dosing strategy in which efficacy was observed delivered a larger dose of QD infusion during the first 3 days of the study and a BID dosing strategy in the next 4 weeks. When the 2-41 days were compared with the appropriate control rats, the reduction in osteolytic bone lesions observed in the fifth group was impressed. It should be noted that in this mode the zoledronate reference configuration administered in response to an equivalent dose estimated to be about 4 times higher than the clinical dose is administered intravenously, and the increased bone density in Group 5 exceeds Physiological values observed in the tibia of treated mice. The correspondingly reduced bone density observed in this mode of treatment with formula (II) shows that BTK inhibition may be a problem for patients with osteolytic bone diseases such as metastatic bone cancer, osteoarthritis and osteoporosis. Provide benefits.

Example 9. BTK performance in different cell types and tissues

Differences in protein expression of BTK throughout various cell types and tissues indicate different rates of BTK synthesis (see Figure 43). In mice, bone marrow-derived B cells showed greater BTK protein expression than B cells from spleen (Pros. Nat'l. Acad. Sci. USA 2000, 97, 2737-2742 by Nisitani et al.). Bone marrow is the tissue chamber in which B cells develop and proliferate, indicating that high BTK levels may be important for effective B cell development. BTK protein expression is also increased following stimulation by B cell receptors (Nisitani et al., PNAS. 2000, 97, 2737-2742). Lymph nodes are the sites in which B cells can be stimulated by antigen binding, resulting in B cells. Activate and increase BTK synthesis. The other part of the high BTK synthesis is the tonsil, which is thought to have high BTK immunohistochemical staining (see The Human Protein Atlas, entry for BTK and Tonsil, available from: proteinatlas.org/ENSG00000010671-BTK/tissue/tonsil).

Example 10. Four-day effect of three anti-inflammatory agents administered by PO and QD in a mouse model in which type II collagen-induced arthritis has been established

This study was designed to determine candidate anti-inflammatory agents of formula (II), ibupotinib or formula (XXI) to inhibit inflammation associated with established type II collagen-induced arthritis (CIA) in DBA/1 mice, The effectiveness of vasospasm formation, cartilage destruction and bone resorption. Formula (II), Ibutinib, Formula (XXI) and BTK Inhibitor (R)-4-(8-Amino-3-(4-(but-2-ynindolyl)morpholine-3- Imidazo[1,5-a]pyridyl -1-yl)-N-(pyridin-2-yl)benzamide is pre-formulated in a vehicle (0.4% HPMC, 0.1% Tween 80, defoamed with polymethoxone) It was administered at 10 ml/kg orally (PO). The candidate anti-inflammatory agent is reconstituted with vortexing or agitation prior to administration. Candidate anti-inflammatory agents were administered daily (QD) to DBA/1 mice via the oral (PO) route.

Arthritis was induced in mice which were genetically susceptible to the DBA/1 strain of this disease by immunization with heterologous type II collagen (CII). In order to develop an experimental model more suitable for studying autoimmune immunity of human rheumatoid arthritis (RA), DBA/1 male mice were injected intradermally (ID) with bovine type II collagen to induce arthritis, such as Trentham. Et al. (Trentham DE, Townes AS, Kang AH Autoimmunity to type II collagen: an experimental model of arthritis. J. Exper. Med. 1977, 146:857-868); and Bendele A (Bendele A, Animal models of rheumatoid arthritis. J. Musculoskelet. Neuronal Interact. 2001, 1(4): 377-85). DBA/1 male mice (n=114) (arthritis day 1) at 6-7 weeks of age and weighing approximately 18-27 grams (average 22 grams) were obtained from Taconic Farms, Inc. The first immunization method for DBA/1 male mice was at least 6 weeks old and housed in 3-5 cages per cage in a polycarbonate shoebox cage with a mesh tip, a sawdust mattress and suspended food and Water bottle. These animals are identified at the trailing end with a distinct ink mark that identifies the animal number. After the selection, all cages are marked with the program number, group number and animal number.

DBA/1 male mice (n=10/arthritis group) were anesthetized with isoflurane (Isoflurane), shaved at the end, and injected intradermally at the end of day 21 and then on day 21 containing bovine II Type 1 collagen (BBP, Lot #7) (1 mg/ml) of 150 microliters of Freund's Complete Adjuvant (Difco, Detroit, MI). A 25-31 day study was performed, arthritis episodes occurred and mice were randomized into treatment groups. Randomization was performed after the swelling (score 1) was clearly established on at least one of the paws and an attempt was made to ensure an equal average score of 0.5-1 for each group at the time of enrollment. Once arthritis is established, DBA/1 male mice are treated with vehicle (0.4% HPMC, 0.1% Tween 80, defoamed with polydimethyloxane) on days 1-14 of arthritis, formula (II) (1, 5 or 25 mg/kg), Ibubinib (1, 5 or 25 mg/kg), formula (XXI) (1 or 5 mg/kg), (R)-4-(8-amino group) -3-(4-(but-2-ynyl) morpholin-3-yl)imidazo[1,5-a]pyridin -1-Base)-N-(pyridin-2-yl)benzamide (5 mg/kg) or the reference compound dexamethasone (Dex, 0.2 mg/kg) QD. DBA/1 male mice were terminated on day 14 of arthritis (3 hours after administration).

The efficacy evaluation of the anti-inflammatory agents administered was based on animal body weight, clinical arthritis score (arthritis score expressed as area under the curve (AUC)), and histopathology in the front paw, hind paw, and knee. Histopathological findings are indicated in 4 paws, only knees or 6 joints including knees. Day 13 was used as the analytical endpoint of body weight change because DBA/1 male mice were fasted overnight before dissection on day 14. All animals survived until the study was terminated.

Formula (II), Ibubinib, Formula (XXI) and (R)-4-(8-Amino-3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazole And [1,5-a]pyridyl Treatment with -1-yl)-N-(pyridin-2-yl)benzamide showed significant benefits in established CIA mode, such as assessment of disease-induced weight loss, clinical arthritis scores, and histopathology of joints Measured. Compared with the vehicle control group, 1 mg formula (II) / kg (*p < 0.05, on days 7-11), 5 mg formula (II) / kg (*d5-14), 25 mg formula ( II)/kg (*d3-14), 1 mg of ibufitinib/kg (*d7-9), 5 mg of ibufenib/kg (*d5-14), 25 mg of ibufibrid/kg ( *d3-14), 1 mg formula (XXI)/kg (*d3-14), 5 mg formula (XXI)/kg (*d3-14) or 5 mg (R)-4-(8-amino group- 3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazo[1,5-a]pyridyl Disease-induced weight loss in DBA/1 male mice given -1-yl)-N-(pyridin-2-yl)benzamide/kg (*d5-14) (eg percent change from baseline) ) is significantly inhibited and tends to be normal.

With formula (II) (5 or 25 mg / kg), ibufenib (5 or The overall weight loss from DBA/1 male mice administered to the study (T1-14) was significantly inhibited in the DBA/1 male mice given either 25 mg/kg or (XXI) (1 or 5 mg/kg).

Compared with the vehicle control group, 5 mg (II) / kg (*d3-14), 25 mg (II) / kg (*d2-14), 5 mg of ibufibrid / kg (*d3 -14), 25 mg of ibufitinib/kg (*d2-14), 1 mg of formula (XXI)/kg (*d8-14), 5 mg of formula (XXI)/kg (*d2-14) or 5 Mg(R)-4-(8-amino-3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazo[1,5-a]pyridin The arthritis score measured daily in DBA/1 male mice given -1-yl)-N-(pyridin-2-yl)benzamide/kg (*d3-14) decreased significantly and became normal. When only those paws (the treated paws) showing clinical symptoms of arthritis at the time of enrollment were considered, 5 mg (II) / kg (*d5-14), 25 mg (II) were compared with the vehicle control group. / kg (*d2-14), 25 mg of ibufitinib/kg (*d3-14) or 5 mg of formula (XXI)/kg (*d5-14) given a significant decrease in the daily score of mice It tends to be normal. When only those paws (prophylactic paws) that did not show clinical symptoms of arthritis at the time of enrollment were considered, 1 mg (II)/kg (*d2, 7-14), 5 mg was compared with the vehicle control group. Formula (II) / kg (*d2-14), 25 mg (II) / kg (*d2-14), 1 mg of ibufenib / kg (*d2-7), 5 mg of ibufibrate / Kg (*d2-14), 25 mg Ibupotini/kg (*d2-14), 1 mg (XXI)/kg (*d2-14), 5 mg (XXI)/kg (*d2- 14) or 5 mg of (R)-4-(8-amino-3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazo[1,5-a]pyrr The daily score of mice given -1-yl)-N-(pyridin-2-yl)benzamide/kg (*d2-14) was significantly decreased and normalized.

Compared with the vehicle control group, 5 mg (II) / kg (down 82%, 99% when calibrated with the initial inclusion score), 25 mg (II) / kg (95%, 115%), 5 mg of ibufitinib / kg (73%, 89%), 25 mg of ibufenib / kg (93%, 112%), 1 mg of formula (XXI) / kg (65%, 79%), 5 mg Formula (XXI) / kg (86%, 104%) or 5 mg of (R)-4-(8-amino-3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazole And [1,5-a]pyridyl The clinical arthritis score AUC of DBA/1 male mice given -1-yl)-N-(pyridin-2-yl)benzamide/kg (74%, 90%) decreased significantly and became normal. When only the treated paws were considered, compared to the vehicle control group, 5 mg (II) / kg (down 64%, 110% when calibrated with the initial inclusion score), 25 mg (II) / kg (89%, 152%), 25 mg of ibufitinib/kg (82%, 141%) or 5 mg (XXI)/kg (66%, 113%) of mice given clinical arthritis score AUC significantly The ground is falling and tends to be normal. When only the prophylactic paws were considered, 5 mg (II)/kg (down 94%), 25 mg (II)/kg (100%), 5 mg of ibufibrate compared with the vehicle control group. /kg (down 96%), 25 mg Ibucitinib/kg (100%), 1 mg formula (XXI)/kg (99%), 5 mg formula (XXI)/kg (100%) or 5 mg ( R)-4-(8-Amino-3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazo[1,5-a]pyridyl The clinical arthritis score AUC of -1-yl)-N-(pyridin-2-yl)benzamide/kg (95%) administered mice decreased significantly and became normal.

Histopathological evaluation confirmed the clinical findings; compared with the vehicle control group, 5 mg (II) / kg (total score decreased 86%), 25 mg (II) / kg (93%), 5 Mgb iibinib/kg (79%), 25 mg Ibupotini/kg (94%), 1 mg (XXI)/kg (73%), 5 mg (XXI)/kg (85%) Or 5 mg of (R)-4-(8-amino-3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazo[1,5-a]pyridin The histopathological parameters of all 6 joints of -1-yl)-N-(pyridin-2-yl)benzamide/kg (75%) administered mice decreased significantly and became normal. There was a significant improvement in knee histopathology parameters in mice given 1 mg (II)/kg compared to 1 mg of ibufitinib/kg. Compared with the vehicle control group, the spleen weight was not affected by formula (II), ibutinib, formula (XXI) or (R)-4-(8-amino-3-(4-(but-2-) Alkynyl)morpholin-3-yl)imidazo[1,5-a]pyridin Significant effect of -1-yl)-N-(pyridin-2-yl)benzamide treatment. BTK occupancy at this time point (which occurred 3 hours after the last oral dose administration) was assessed using spleen cell preparations; observed in mice treated with formula (II), ibufibrate and formula (XXI) Similar to BTK occupation.

Results of treatment with Dex As expected, treatment with Dex significantly improved arthritis.

Vehicle-treated control mice began to lose weight at the onset of arthritis (as measured by percent change from baseline) and reached a peak of 10.86% on day 13 of the study (using day 13 as the endpoint of the analysis of body weight changes) Mice were fasted overnight before dissection on day 14.)

Compared with the vehicle control group, 1 mg/kg formula (II) (*p<0.05, on days 7-11), 5 mg formula (II)/kg (*d5-13), 25 mg formula ( II)/kg (*d3-13), 1 mg ibbutinib/kg (*d7-9), 5 mg ibbutinib/kg (*d5-13), 25 mg ibbutinib/kg ( *d3-13), 1 mg formula (XXI)/kg (*d3-13), 5 mg formula (XXI)/kg (*d3-13) or 5 mg (R)-4-(8-amino group- 3-(4-(but-2-ynindolyl)morpholin-3-yl)imidazo[1,5-a]pyridyl Disease-induced weight loss in mice given -1-yl)-N-(pyridin-2-yl)benzamide/kg (*d5-13) was significantly inhibited and normalized. Mice administered with formula (II) (5 or 25 mg/kg), Ibutiinib (5 or 25 mg/kg) or formula (XXI) (1 or 5 mg/kg) were selected from the study (d1) -13) The overall weight reduction was significantly suppressed.

The experimental design is shown in Table 1.

The results are summarized in Table 2.

In formula (II), ibufenib, formula (XXI) and (R)-4-(8-amino-3-(4-(but-2-ynindolyl)morpholin-3-yl) Imidazo[1,5-a]pyridyl A similar BTK occupancy was observed in mice treated with -1-yl)-N-(pyridin-2-yl)benzamide (〝BTK Inh-A〞), as exemplified in Figure 44. Evaluation of BCR signaling inhibition by BTK evaluated CD86 and CD69 by in vitro stimulation using IgM splenocytes and functional responses stimulated by BCR. Figure 45 and Figure 46 show the formula (II), Ibubinib, formula (XXI) and (R)-4-(8-amino-3-(4-(but-2-ynindolyl)morpholine -3-yl)imidazo[1,5-a]pyridinium -1-yl)-N-(pyridin-2-yl)benzamide (〝BTK Inh-A〞)-treated mice ("BTK Inh-A") have a dose response that reduces the transmission of BCR-mediated media. Instead, no effect on BCR signaling was observed in mice treated with dexamethasone. The similarity in the level of functional inhibition of BCR by equations (II) and (XXI), together with a similar BTK occupancy, reflects a similar mode of action for BTK active position kinases.

Example 11. Effect of Formula (II) on PD, QD or BID Administration for 14 Days in Mice with Type II Collagen Arthritis

This study was designed to determine covalent BTK inhibitors. (II) inhibits acute inflammation, vasospasm, cartilage destruction associated with established type II collagen-induced arthritis (CIA) in DBA/1 mice. The effectiveness of bone resorption. Arthritis was induced in mice which were genetically susceptible to the DBA/1 strain of this disease by immunization with heterologous type II collagen (CII). In order to develop an experimental model more suitable for studying autoimmune immunity of human rheumatoid arthritis (RA), DBA/1 male mice were injected intradermally (ID) with bovine type II collagen to induce arthritis, such as Trentham. Et al. (Trentham DE, Townes AS, Kang AH Autoimmunity to type II collagen: an experimental model of arthritis. J. Exper. Med. 1977, 146: 857-868); and Bendele A (Bendele A, Animal models of rheumatoid arthritis .J. Musculoskelet. Neuronal Interact. 2001, 1(4): 377-85) reported.

After acclimation, 6-7 weeks old DBA/1 male mice (n=10/arthritis group) were injected intradermally with Freund's complete adjuvant containing 1 mg/ml of bovine type II collagen (Difco) , Detroit, MI) and immunized. The immunization system was performed on day 0 and again on day 21. A study of 25-26 days was performed and mice were randomized into treatment groups on the 8th day after the onset of arthritis. Day 8 generally represents the acute disease peak state in this model (score 4/joint is affected); the treatment group was weighed at an equal score of approximately 3.5 on enrollment. Oral administration was started on the 8th day of arthritis. Each group was given vehicle (0.4% HPMC, 0.2% Tween 80), 25 mg formula (II) / kg QD, 12.5 mg formula (II) / kg BID or 0.2 mg reference compound dexamethasone (Dex) / Kg QD treatment. These animals were fasted overnight on the 20th day of arthritis prior to dissection on the 21st day of arthritis (13 days after enrollment). Clinical scores were given for each paw (right front, left front, right rear, left posterior) on day 1-21 of arthritis.

Efficacy assessments were based on animal body weight, clinical arthritis scores (mechanical arthritis scores under the curve area (AUC)), and histopathology in the front paws, hind paws, and knees. Histopathological findings are indicated in 4 paws, only knees or 6 joints including knees. Day 19 was used as the analytical endpoint of body weight change because DBA/1 male mice were fasted overnight before dissection on day 21. All animals survived until the study was terminated. Formula (II) was completely resistant to the conditions of this study and there was no adverse effect from treatment.

Treatment with BTK inhibitors (25 mg/kg QD or 12.5 mg/kg BID) resulted in significant improvements in established CIA patterns, such as assessment of disease-induced weight loss, clinical arthritis scores, and histopathology of joints. Determination. The results of QD and BID treatment were mostly similar. Except for body weight, the weight of mice given 25 mg/kg QD was significantly increased compared with the treatment of 12.5 mg/kg BID, and the spleen weight was 12.5. The spleen weight of mice given mg/kg BID was significantly reduced and normalized.

Compared with the vehicle control group, 25 mg (II) / kg QD (*p < 0.05, day 11-21) or 12.5 mg formula (II) / kg BID (*p < 0.05, 9- The 21-day) treated mice scored a significant decrease in arthritis scores daily and became normal. Treatment with formula (II) treated with BID had a stronger initial decrease in arthritis score; however, both drug delivery configurations had similar prolonged therapeutic effects.

The area under the curve (AUC) of the clinical score was calculated from the start of administration (d8) to the end of the study (d21). The clinical arthritis score AUC of mice given 25 mg (II) / kg QD (56% decrease) or 12.5 mg (II) / kg BID (59% decrease) was significantly higher than that of the vehicle control group. It falls and tends to be normal. Arthritis scores of mice treated with 25 mg (II)/kg QD, 12.5 mg (II)/kg BID or Dex compared to the vehicle control group when calibrated at the initial enrollment score (d8) AUC also dropped significantly.

The fasted mice were dissected and the final serum, forepaw, hind paw and knee were collected into 10% neutral formalin buffer (NBF) for microscopy. Get the spleen and weigh it.

The absolute weight of the spleen of the vehicle control mice was significantly increased as compared with the simple control group. The absolute weight of the spleen of mice administered with Dex or 12.5 mg of formula (II) per kilogram of BID was significantly reduced compared to the vehicle control group, with a reduction of 156% and 64%, respectively. Compared with the treatment of 25 mg (II) / kg QD treatment group, given 12.5 mg (II) / kg BID The absolute weight of the spleen of the mice was also significantly reduced.

Mice given 25 mg (II)/kg QD (56% overall score) and 12.5 mg (II)/kg BID (53%) or Dex group (57%) compared with the vehicle control group The 6 joint histopathological parameters decreased significantly and became normal. The mean periosteal bone width of the 6 joints of all groups was significantly reduced and normalized compared to the vehicle control group.

Compared with the vehicle control group, DBA/1 male mice treated with 25 mg of formula (II)/kg QD had significantly decreased knee inflammation (53% reduction), vasospasm formation (82%), and cartilage destruction (28). %), bone resorption (82%) and total knee score (51%). Mice treated with 12.5 mg of formula (II) per kilogram of BID had significantly reduced knee inflammation (49%), vasospasm formation (80%), bone resorption (78%), and total knee score (45%). DBA/1 male mice treated with Dex had significantly reduced knee inflammation (57%), vasospasm formation (86%), cartilage destruction (39%), bone resorption (88%), and total knee score (57%). ).

When DBA/1 mice were administered in the CIA mode after an acute inflammatory episode, the study showed similar efficacy between the divided dose (12.5 mg/kg BID) and the 25 mg (II)/kg QD dose. . Formula (II) is active at established disease sites, including joints of the paw and knee, while improving clinical signs and improving weight gain during the course of treatment.

The BID dosing configuration has a more pronounced effect on splenomegaly than the QD dosing configuration of BTK inhibitors. In addition, clinical and histopathological evaluation of collagen-induced arthritis in DBA/1 mice showed a total daily delivery of 25 mg/kg in QD or BID. The dosage of formula (II) is improved after treatment. A similar degree of improvement was observed in this acute mode of active rheumatoid arthritis with formula (II) and Dex (positive control).

The results are summarized in Table 3.

Example 12. Efficacy of kidney inflammation in the MRL/MpJFASlpr mouse model of systemic lupus erythematosus of formula (II)

This study was designed to determine the effect of systemic lupus erythematosus (SLE) in MRL/MpJFASlpr mice treated with a daily (QD) oral (PO) administered anti-inflammatory agent (II). Formula (II) was pre-formulated in a vehicle (0.4% HPMC, 0.1% Tween 80, defoamed with polydimethyloxane). MRL/MpJFASlpr female mice were administered daily (QD) by vehicle or formula (II) (1, 5 or 25 mg/kg) or by reference compound cyclophosphamide (15 mg/kg) Administered by intraperitoneal (IP) route QD. In administration The candidate anti-inflammatory agent was previously reconstituted with vortexing or agitation. Candidate anti-inflammatory agents were administered to MRL/MpJFASlpr mice for two weeks.

MRL/MpJFASlpr female mice (n=50) (about 12 weeks old mice) 8-9 weeks old and weighing 28-41 grams (average 34 grams) at the time of enrollment were from The Jackson Laboratory, Bar Harbor, Maine (Stock No. 000485) Obtained. The mice were housed in 3-5 cages per cage in a polycarbonate shoebox cage with a mesh top, a sawdust mattress and suspended food and water bottles. The combination was not given. The experimental design is shown in Table 4.

When the mice were 12 weeks old (day 0 of the study), MRL/MpJFASlpr female mice (n=10/group) were randomly divided into 5 groups by body weight, as indicated above. Treatment was started after randomization and continued for 12 weeks (12 week to 23 week old mice).

The study was started at week 1 and then urine proteinuria from each animal was tested weekly using a Clinitech Multistick test paper (Bayer). Obvious clinical signs, dying status, and mortality were also observed daily. A disease episode occurs at about 12-14 weeks of age. Efficacy assessment was based on animal weight, proteinuria analysis, lymph node score, skin lesion score, organ weight, anti-dsDNA titer intensity, clinical chemistry parameters, and histopathological evaluation of the kidney. There were 3 mice in the 10 vehicle disease control group and One of 10 mice in the formula (II) (5 mg/kg) sacrificed or died before the study was terminated. All other mice survived to the end of the time course.

Once 50% of the animals in the vehicle-treated group had significant lesions, lymph nodes (neck, arm and groin) and skin lesion scores were recorded for all animals starting at week 4 of the study. Any animal showing signs of dying is immediately terminated. At the time of dissection (3 hours after the dose, 23-week-old mice), all remaining animals were anesthetized with isoflurane and bled by serum and plasma (Li heparin) via cardiac puncture. The animals were bled for blood removal and then euthanized by cervical dislocation. Collect and weigh the spleen, kidneys (pairs) and lymph nodes. The kidneys were collected into 10% neutral formalin buffer (NBF). The spleen was placed in RPMI 1% FBS medium to isolate spleen cells. Serum samples for potential clinical chemistry analysis were stored frozen at -80 °C until shipped to Antech Diagnostics. Plasma samples were stored frozen at -80 ° C and anti-dsDNA IgG analysis of mice was performed by ELISA.

The clinical chemistry parameters of 3 mice that were killed in the mid-term (dying) were measured: vehicle disease control group animals #1 and #6 and formula (II) (5 mg/kg) group animal #4. Blood samples from isoflurane anesthetized animals were drawn via cardiac puncture to serum for clinical chemistry to separate microtubes. Samples were shipped to Antech Diagnostics for analysis.

As shown in the table below, treatment with formula (II) showed a significant and dose-responsive beneficial effect on lupus nephritis in MRL/MpJ-FASlpr mice compared to the vehicle disease control group, as assessed by evaluation Proteinuria score, kidney weight, mesenteric lymph node weight, and including significantly decreased glomerular diameter, glomerular percentage with crescent, protein deposition Cast) scores were determined by histopathological scores for scoring, vasculitis, and histopathology total scores. Body weight measurements, lymph node scores, skin lesion scores, spleen weight, cumulative lymph node weight, and mouse anti-dsDNA IgG levels in plasma treated with formula (II) were not significantly different from vehicle disease control groups. Results of treatment with cyclophosphamide As expected, this treatment resulted in significant beneficial effects on clinical and histopathological parameters.

The results are shown in Table 5.

The weight gain of all groups during the course of the study (as measured by the percentage change from baseline). When all animals were considered (including those that died in the medium term), there was a significant decrease in mice at 14-16 weeks of age and 19 weeks of age in cyclophosphamide-treated mice compared to the vehicle-treated disease control group. Weight gain. When considering only those animals that survived the study termination (terminating animals), 14-17 week old and 19-20 week old mice were compared in the cyclophosphamide treated mice compared to the vehicle disease control group. Has a significantly reduced weight gain. From week 1 to week 5, all animals in the vehicle disease control group had an average weight gain of 3.39 grams and an average weight gain of 3.85 grams in the terminating animals. Mice administered with cyclophosphamide had a significantly reduced weight gain of 1.03 grams during the same period of time. Changes in body weight of mice treated with formula (II) There was no significant difference in the vehicle disease control group.

The vehicle disease control group had an increased average urinary protein score during the course of the study. When all animals were considered, 14-15 weeks old and 21-22 weeks old mice were given in 25 mg of the (II)/kg treated mice and administered with cyclophosphamide in comparison with the vehicle disease control group. The average urine protein score of mice aged 14-23 weeks was significantly decreased in the mice. When only the terminating animals were considered, compared to the vehicle disease control group, in the 25 mg (II)/kg treated mice, 22 weeks old mice and the cyclophosphamide administered mice were 14 The mean urinary protein scores of the 16-week-old and 19-22 week-old mice were significantly reduced. The vehicle disease control group had an increased mean lymphadenopathy score during the course of the study. The lymph node enlargement scores of the 15-23 week old mice were significantly reduced in the cyclophosphamide administered mice compared to the vehicle disease control group, regardless of whether all animals or only the terminating animals were considered. The lymph node enlargement score of the mice treated with the formula (II) had no significant effect compared with the vehicle disease control group. The vehicle disease control group had an increased skin lesion score during the course of the study. The skin lesion scores of mice at 20-23 weeks of age were significantly reduced in the cyclophosphamide administered mice compared to the vehicle disease control group, regardless of whether all animals or only terminating animals were considered. The skin lesion score of the mice treated with formula (II) had no significant effect compared to the vehicle disease control group.

Vehicle disease control mice had a 70% survival rate at the end of the study. Mice treated with 5 mg of formula (II) per kilogram had a 90% survival rate at the end of the study. All other groups have a 100% survival rate. When all animals were considered, the absolute weight of the kidneys of the mice administered with cyclophosphamide was significantly decreased (down 23%) compared to the vehicle disease control group. When only test When considering the terminating animals, 5 mg (II) / kg (16%), 25 mg (II) / kg (19%) or cyclophosphamide (32%) compared with the vehicle disease control group. The absolute weight of the kidney of the treated mice decreased significantly.

The absolute weight of the spleen of mice administered with cyclophosphamide was significantly reduced compared to the vehicle disease control group (77% and 82%, respectively, for all animals and terminating animals). The kidney weight of the mice treated with formula (II) was not significantly different from that of the vehicle control group.

The absolute weight of the cumulative lymph nodes of mice administered with cyclophosphamide was significantly reduced compared to the vehicle disease control group (87% and 90%, respectively, for all animals and terminal animals). The cumulative lymph node weight of the mice treated with formula (II) was not significantly different from that of the vehicle control group. When all animals were considered, the absolute weight of the mesenteric lymph nodes of the mice administered with cyclophosphamide was significantly decreased (by 76%) compared to the vehicle disease control group. When only the terminating animals are considered, 5 mg (II) / kg (52%), 25 mg (II) / kg (49%) or cyclophosphamide (82 mg) compared to the vehicle disease control group. %) The absolute weight of the mesenteric lymph nodes of the treated mice decreased significantly. The vehicle disease control group had a mouse anti-dsDNA IgG content in plasma of 3,078.59 kU/ml. The anti-dsDNA IgG content in mice treated with cyclophosphamide was significantly reduced (by 76%) compared to the vehicle disease control group. The anti-dsDNA IgG content in mice treated with formula (II) had no significant effect compared to the vehicle disease control group.

When comparing all animals, serum clinical chemistry assessment revealed significantly increased albumin (ALB), glucose (GLU) and sodium in mice administered at 1 mg (II)/kg compared to the vehicle disease control group. /potassium ratio (Na/K) and significantly decreased blood urea nitrogen (BUN), BUN/creatinine, phosphorus (P), potassium (K), cholesterol (CHOL) and amylase (AMY). When only the terminating animals were compared, mice administered at 1 mg of formula (II)/kg had significantly decreased BUN and BUN/creatinine compared to the vehicle disease control group. When comparing all animals, mice treated with 5 mg of formula (II)/kg had significantly increased ALB, GLU, calcium (CA) and Na/K and significantly decreased BUN compared to the vehicle disease control group. BUN/creatinine, K, CHOL and AMY. When only the terminating animals were compared, mice treated with 5 mg of formula (II)/kg had significantly increased ALB, albumin/globulin ratio (A/G), GLU and compared with the vehicle disease control group. Na/K and significantly decreased BUN, BUN/creatinine and K. When comparing all animals, mice treated with 25 mg of formula (II)/kg had significantly increased ALB, GLU, calcium (CA) and Na/K, and significantly decreased BUN, compared with the vehicle disease control group. BUN/creatinine, K, CHOL and AMY. When only the terminating animals were compared, mice treated with 25 mg of formula (II) per kilogram had significantly increased ALB and CA and significantly decreased BUN and BUN/creatinine compared to the vehicle disease control group. Regardless of all animals or terminating animals, mice treated with cyclophosphamide had significantly increased ALB, A/G, alkaline phosphatase (ALK), GLU and Na/K compared to the vehicle disease control group. And significantly decreased globulin (GLOB), BUN, BUN/creatinine, K and AMY.

When all animals were considered (including those that died in the medium term), mice treated with 1 mg of formula (II)/kg had a significantly reduced glomerular diameter (down 43%) compared to the vehicle-borne disease control group. And the percentage of glomeruli with a crescent (down 97%). Compared with the vehicle disease control group, 5 mg of mice treated with (II)/kg had significantly decreased glomerular diameter (60%), glomerular score (58%), glomerular percentage with ecliptic (99%), protein deposition Score (92%), vasculitis (52%), and histopathology total score (63%). Mice treated with 25 mg (II)/kg had significantly decreased glomerular diameter (73%), glomerular score (76%), and glomerular crescents compared with vehicle control group. Score (100%), percentage of glomeruli with a crescent (100%), protein deposition score (98%), interstitial nephritis (59%), vasculitis (52%), and histopathology total score ( 75%). Mice treated with cyclophosphamide had significantly decreased glomerular diameter (89%), glomerular score (88%), and glomerular crescent score (100%) compared with the vehicle disease control group. ), glomerular percentage (100%) with a crescent, protein deposition score (90%), interstitial nephritis (74%), vasculitis (82%), and histopathology total score (86%).

When only the terminating animals were considered, the mice treated with 1 mg of the formula (II)/kg had a significantly decreased percentage of glomeruli with a crescent (a 90% decrease) compared to the vehicle disease control group. Compared with the vehicle disease control group, mice treated with 5 mg of formula (II)/kg had a significantly decreased glomerular diameter (46%), a glomerular percentage with a crescent (98%), and protein. Sediment score (90%) and histopathology total score (54%). Mice treated with 25 mg (II)/kg had significantly decreased glomerular diameter (63%), glomerular score (72%), and glomerular crescents compared with vehicle control group. Score (100%), glomerular percentage (100%) with crescent, protein deposition score (97%), interstitial nephritis (51%), vasculitis (47%), and histopathology total score ( 68%). Cyclophosphamide compared with the vehicle disease control group Treated mice had significantly decreased glomerular diameter (85%), glomerular score (86%), glomerular crescent score (100%), and glomerular percentage with crescent (100%) ), protein deposition score (86%), interstitial nephritis (70%), vasculitis (80%), and histopathology total score (82%).

Example 13. Controlled Release Formulation of BTK Inhibitors

It can prepare 10-50% of formula (II), 10-33% microcrystalline cellulose, 1-10% modified starch, 0.1-10% crospovidone, 0.05-1% An anhydrous particle of formula (II) of magnesium stearate and 0-1% fumed cerium oxide.

The uncoated particles are partially sprayed on a fluid bed using a top spray of 1:1 poly(methacrylic acid-co-ethyl acrylate), 1:1 poly(methacrylic acid-co-methyl methacrylate) or 1:2 poly(methacrylic acid-co-methyl methacrylate) was coated to an increase of 2% by weight. An aliquot of the coated granules is blended with the uncoated granules and filled into hard gelatin capsules to a target of 100 mg of the total dose of formula (II). The 25 mg dose was delivered in a pulsed manner to the stomach, duodenum, jejunum, and colon.

Example 14. Extended Release Formulations of BTK Inhibitors

Will contain 40-60% of formula (II), 15-30% of microcrystalline cellulose, 1-10% modified starch, 0.1-10% crospovidone, 0.05-1% stearic acid Magnesium and 0-1% fumed cerium oxide of the anhydrous particles of formula (II) are blended with ultragranular 4000cP hydroxypropyl methylcellulose substituted 2208 (10-25% by weight) and Then with 0.05-1% magnesium stearate lubricating. The blend was then compressed using a rotary tablet machine equipped with a 10 mm round lenticular mold.

Example 15 - Clinical observation of the effect of BTK inhibitors on skin diseases

Clinical studies have shown that targeting BCR signaling by inhibiting BTK produces significant clinical benefits in patients with various types of leukemia and lymphoma. Formula (II) achieves significant oral bioavailability and efficacy with preclinical features as described above. The aim of this study was to evaluate the safety and efficacy of a second generation (II) BTK inhibitor in the treatment of individuals with chronic lymphocytic leukemia (CLL) and small lymphoblastic lymphoma (SLL).

The main objectives of the clinical study are as follows: (1) establishing the safety and MTD of oral administration of formula (II) in individuals with CLL/SLL; and (2) measuring the drug of formula (II) administered orally. Kinetics (PK) and identification of its major metabolites; and (3) measurement of pharmacodynamic (PD) parameters, including drug occupancy of BTK, target enzymes, and effects on biomarkers of B cell function. A secondary objective of clinical studies is to assess tumor response in patients treated with formula (II). In addition, the effect of formula (II) on other patient characteristics (such as skin diseases) was evaluated for the specific patient of the registration study.

This study was a multicenter, open-label, non-randomized, sequential group, dose escalation study. Evaluate the following dose groups:

Team 1:100 mg / day 28 days (=1 cycle)

Team 2: 175 mg / day 28 days (=1 cycle)

Team 3: 250 mg / day 28 days (=1 cycle)

Team 4:400 mg / day 28 days (=1 cycle)

Team 5:450 mg / day 28 days (=1 cycle)

Team 6: measured in milligrams per day for 28 days (=1 cycle)

Each team is registered with 6 individuals in each team. If observed during the period 1 in the team The 1-dose dose-limiting toxicity (DLT) is increased until the next group continues. If 4 of the 6 individuals registered in the team complete cycle 1 without experiencing DLT and the remaining 2 individuals are completing the assessment, the individual may be registered with the next team. If observed during cycle 1 The 2-digit DLT suspends this dose and higher dose administration and establishes MTD as previously established. MTD is defined as the daily maximum dose of less than 33% of individuals undergoing DLT during cycle 1. When the MTD is reached or greater than the full BTK occupancy at 3 dose values, whichever comes first, the dose escalation is ended. Full BTK occupancy is defined as >80% of the formula (II) active position occupancy (average of all individuals in the team) at 24 hours post dose. If it is necessary to increment to Team 6, the dose is determined based on the overall data from Teams 1 through 5, which includes safety, performance, and PK/PD results. The dose of Team 6 does not exceed 900 mg/kg.

Treatment with formula (II) can last for > 28 days until disease progression or unacceptable drug-related toxicity occurs. Individuals with disease progression were removed from the study. All individuals who discontinued the study drug had a 30 (±7) day safety follow-up visit after the last study drug dose, unless the individuals started another cancer therapy within that time period. Radiological tumor assessment will be performed at screening and at the end of Cycle 2, Cycle 4 and Cycle 12, as well as at the discretion of the investigator When the situation is decided. Complete response (CR) needs to be confirmed by bone marrow analysis and radiological tumor assessment. Individuals who remained in the study for >11 months were required to undergo mandatory bone marrow extraction and biopsy and radiological tumor assessment simultaneously in cycle 12.

All individuals have a standard hematology, chemical and urinalysis safety review conducted at screening. This study also included pancreatic functional assessment (serum amylase and serum lipase) due to pancreatic findings in the GLP rat toxicity study on day 28. Once dosing is initiated, all individuals are assessed weekly, once a week, once every other week, and then monthly for safety. Blood samples were collected during the first week of treatment for PK/PD assessment. The ECG is performed at the time of screening and on days 1-2, 8, 15, 22, 28 of cycle 1, on days 15 and 28 of cycle 2, and then until cycle 6 on a monthly basis. Only the screened ECG was repeated three times. A single ECG test is then performed unless a repeated ECG test is required.

Dose-limiting toxicity is defined as any of the following events (assuming it is not related to disease progression): (1) any grade 3 continued non-hematologic toxicity (except for hair loss), although a single course of standard outpatient symptomatic treatment (eg, grade 3 diarrhea that responds to a single therapeutic dose of Imodium® is not considered DLT); (2) grade 3 extended corrected QT interval (QTc) as determined by central ECG laboratory overread; (3) continuation of treatment for >7 days after discontinuation of treatment without growth factor or after discontinuation of treatment and dependence on growth factors Neutral hypothyroidism with a grade of >5 days (absolute neutrophil count [ANC] <500/μl) (ie, a neutrophil of level 4 that does not last as long as specified) Hypoxemia is not considered to be DLT), (4) Platelet hypoxia (platelet count <20,000/μl) that lasts for >7 days after discontinuation of treatment or requires grade 4 of infusion (ie, does not continue as specified) Long-term platelet hypoxia of grade 4 is not considered to be DLT), and (5) delayed administration due to toxicity > 7 consecutive days.

The assessment procedure is as follows: All days of the statement have the following meaning: the given day or +/- 2 days from the given day. Physical examination (including signs of life and weight) is at the time of screening, days 1, 8, 15, 22 and 28 of period 1, periods 15 and 28 of period 2, and days 28 of period 3 to 24, And when tracking (after the last dose). Screening physical examinations include, at a minimum, the general appearance of the individual, height (screening only) and body weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. A physical examination of the sign is then carried out. Vital signs (blood pressure, pulse, respiratory rate, and body temperature) are assessed after the individual has rested in the seat. The Eastern Cooperative Oncology Group (ECOG) status is at the time of screening, on days 1, 8, 15, 22, and 28 of cycle 1, and on days 15 and 28 of cycle 2, Published ECOG performance status indicators as described in MMOken et al., Am. J. Clin. Oncol. 1982, 5, 649-655, on day 28 of the period 3 to 24, and at the time of tracking. The ECG test is at the time of screening, on days 1, 8, 15, 22 and 28 of cycle 1, on days 15 and 28 of cycle 2, on days 28 of cycle 3 to 24, and during tracking get on. At the time of screening, the 12-lead ECG test was repeated three times ( 1 minute interval). The calculated QTc average of 3 ECGs must be < 480 microseconds to be a qualified value. A single ECG system on day 1 of cycle 1 and day 8 of cycle 1 was performed before administration and at 1, 2, 4, and 6 hours after administration. A single ECG on day 2 of cycle 1 was performed prior to dosing. A single ECG line on days 15, 22, and 28 of cycle 1 was performed 2 hours after dosing. A single ECG beginning with cycle 2 is performed at each visit. Before studying the relevant ECG, the individual should be in a supine position and rested for at least 10 minutes. Two consecutive machine readings of QTc > 500 microseconds or above the baseline > 60 microseconds require a central ECG review. Hematology (including the number of whole blood cells with cell classification and the number of platelets and the number of reticulocytes) is at the time of screening, on days 1, 8, 15, 22, and 28 of period 1, and during period 2 15 and 28 days, on day 28 of the period 3 to 24, and at the time of tracking. Serum chemistry at screening, on days 1, 8, 15, 22, and 28 during cycle 1, on days 15 and 28 during cycle 2, on days 28 from cycle 3 to 24, and during tracking assessment. Serum chemistry includes albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, potassium , sodium, total bilirubin, total protein and uric acid. Cell number and serum immunoglobulin line were performed at screening, on day 28 of cycle 2, and every 6 months thereafter until the final dose, and included T/B/NK/monocyte number (CD3, CD4, CD8, CD14, CD19, CD19, CD16/56 and other cell numbers as needed) and serum immunoglobulins (IgG, IgM, IgA and total immunoglobulin). Bone marrow withdrawal is performed in cycle 12. Pharmacodynamic samples were taken on days 1, 2 and 8 of Cycle 1 and at follow-up. On days 1 and 8, pharmacodynamic samples were drawn before administration and 4 hours after administration (±10 minutes), and on day 2, pharmacodynamic samples were drawn prior to administration. The pharmacokinetic samples were drawn on days 1, 2, 8, 15, 22 and 28 of cycle 1. The pharmacokinetic samples on day 1 of cycle 1 were drawn before dosing and at 0.5, 1, 2, 4, 6 and 24 hours after dosing (before dosing on day 2). Samples on day 8 of cycle 1 were drawn before dosing and at 0.5, 1, 2, 4 and 6 hours after dosing. On days 15, 22 and 28 of cycle 1, the PK sample was drawn prior to dosing and the second PK sample was taken prior to ECG acquisition (which was 2 hours after dosing) (up to 10 minutes prior). The pretreatment radioactive tumor assessment was performed within 30 days prior to the first dose. Computerized tomography (CT) scans of the chest, abdomen, and pelvis are required (with contrast unless contraindicated). In addition, individuals with SLL must undergo positron emission tomography (PET) or PET/CT. The radiological tumor assessment was mandatory at the end of cycle 2 (-7 days), cycle 4 (-7 days), and cycle 12 (-7 days). Otherwise, the radiological tumor assessment is freely considered by the investigator. CT of the chest, abdomen, and pelvis of individuals with CLL (with contrast unless contraindicated) is required. In addition, PET/CT of individuals with SLL is required. It is required to confirm the complete response (CR) by both bone marrow and radioactivity. The clinical assessment of tumor response should be performed at cycle 6 and at the end of every 3 months. Molecular markers are measured at screening and include interphase cytogenetics, stimulated karyotypes, IgHV mutation status, ZAP-70 methylation, and beta-2 microglobulin values. Urinalysis is performed at screening and includes pH, ketone, specific gravity, bilirubin, protein, blood, and glucose. Other assessments, including informed consent, qualifications, medical history, and pregnancy tests, are performed at the time of screening.

The research process is a continuous team increment. Each team consists of 6 individuals. The size of the sample studied was from 24 to 36 individuals depending on the dose escalation to subsequent teaming. Team 1 (N=6) consisted of Formula (II) with 100 mg QD over 28 days. Team 2 (N=6) consisted of Formula (II) with 175 mg QD over 28 days. Team 3 (N=6) consisted of Formula (II) with 250 mg QD over 28 days. Team 4 (N=6) consisted of Formula (II) with 350 mg QD over 28 days. Team 5 (N=6) was subjected to formula (II) with 450 mg QD for 28 days. Team 6 (N=6) consisted of Formula (II) for 28 days at the dose QD to be determined. The dose value of Team 6 is determined based on safety and the effectiveness of Teams 1 to 5 and does not exceed 900 mg/day. The increment is terminated by the MTD team or 3 values greater than the full BTK occupancy (which is observed first). An additional study team team explored 100 mg BID administration. Treatment with oral formula (II) can last for more than 28 consecutive days until disease progression or unacceptable drug-related toxicity occurs.

The criteria for inclusion in the study are as follows: (1) Have a confirmed CLL/SLL 18-year-old male and female, tied 2 times of CLL/SLL recurrence or become recalcitrant after prior treatment; however, if the individual relapses or becomes recalcitrant after 1 CLL/SLL treatment, the individual with 17p deletion is eligible; (2) body weight 60 kg; (3) ECOG performance status 2; (4) if sexually active and able to have a child, agree to contraception during the study period and 30 days after the last dose of study drug; (5) willing and able to participate in all the assessments and procedures required in this research project, Includes no difficulty in swallowing capsules; or (6) understanding the purpose and risks of the study and providing signed and dated informed consent and the ability to authorize the use of protected health information (according to national and local individual privacy regulations).

The dosage forms and strengths of formula (II) used in clinical studies were prepared using standard pharmaceutical grade excipients (microcrystalline cellulose) and each contained 25 mg of hard gelatin capsules of formula (II). The capsule color is Swedish orange. The path is administered as an oral (per os or PO). The dosage configuration is once daily or twice daily, on a fasting basis (defined as 2 hours before dosing and 30 minutes after dosing), as specified by the team.

Further details of the study are described in WO 2015/110923, the disclosure of which is incorporated herein by reference.

Individual 1 in the aforementioned clinical study was a male CLL patient with a history of psoriasis skin disease for 60 years. Individual 1 has psoriasis since the age of 25, the joints are not affected, and there are diffuse plaques in the trunk and limbs. It has severe psoriasis and ~30% of the body surface area (BSA) is affected. It has been treated with several systemic therapies in the past, including 2010 clinical studies of etanercept, adalimumab, and experimental agents. It initially responded to etanercept but continued to erupt and was treated by a dermatologist before being enrolled in a clinical study. His treatment history includes topical medications, and recently included Taclonex (calcipotriene/betamethasone diproprionate) without much skin lesion improvement.

When starting treatment with formula (II), the skin sign of individual 1 began to improve rapidly. There were some improvements during the first month of treatment (detected by the individual); the consultation dermatologist confirmed that the lesion was less troublesome/redness before it subsided. During the first 6 months of treatment, the psoriasis of the individual 1 was almost relieved. It is. It has clean skin at cycle 10 (10 months after formula (II)). This result indicates that 90% of the psoriasis area and severity index (PASI90) was achieved by the individual at the 10th month of visit. The only remaining is some scaly in the same area that was once affected by psoriasis. The history of 30+ years of psoriasis skin disease, including multiple TNF inhibitors and multiple systemic treatments with inappropriately administered active topical therapy, indicates that the long-term disease is not relieved by the placebo effect or its CLL. Improve.

Changes in serum cytokines and chemokine levels in individual 1 during the first 4 weeks of administration demonstrated a systemic reduction in inflammatory cytokines associated with psoriasis. Compared with the individual's baseline level, especially in the treatment of interleukin-6 (IL-6), MIP-1α, MIP-1β, MCP-1, TNFA, TARC, CXCL5, CD40L, TRAIL, EGF and CXCL1 28 days down.

Individual 2 was enrolled in a clinical study similar to that described above and also experienced the release of moderate to severe plaque psoriasis (cases of sputum red sputum) when treated with formula (II). The disease history of an individual in most of his adulthood includes extensive body surface area involvement, mainly in the back and thighs. The individual's disease is rapidly cleared after starting treatment with formula (II).

The use of formula (II) to clinically relieve psoriasis is unexpected, as it is generally considered that the most important treatment for psoriasis is the selectivity of formula (II) for BTK and its lack of off-target effects on T cells. The BTK inhibitor of formula (II) can instead achieve its results by inhibiting novel mechanisms of BTK in other cells, including infiltrating neutrophils, macrophages, mast cells and dendritic cells. Some tyrosine kinase inhibitors used to treat malignant diseases (such as Imatinib can cause psoriasis to worsen. Dasatinib is a multi-kinase inhibitor that has been reported to inhibit BTK, but dasatinib has not been reported to improve psoriasis. Bonatinib causes a great degree of dry skin and induces a disease that is very psoriasis in individuals without a history of skin disease. Formula (II) thus demonstrates the surprising and unexpected results of successful removal of moderate to severe psoriasis.

Example 16. Topical formulations of BTK inhibitors

A topical formulation containing from 1 to 10% of the emollient substrate of formula (II) in an oil phase and an aqueous phase can be formulated as follows. Formula (II) can be introduced into either phase by means of a top high shear rotor-stator homogenizer. The oil phase can be heated to 60 ° C to reduce the viscosity to ensure uniform distribution of formula (II). The cream is then emulsified by homogenization and at the same time slowly introduced into the premixed aqueous phase, with or without a vacuum to prevent air incorporation. Alternatively, the two phases can be ground using a colloid mill or a high pressure piston homogenizer. If the input solid of formula (II) does not rapidly pass through the colloid mill to reduce the particle size, it should have a particle size distribution of D90 of less than 100 microns and D10 of greater than 5 microns prior to introduction into the substrate.

Formula (II) can also be formulated as a low dose ointment having a drug loading of 0.05-1% w/w. The polyethylene glycol-based ointment can be prepared by softening 25-40% w/w of polyethylene glycol 4000 at 60 ° C and combining with 50-70% of polyethylene glycol 400. Powder of formula (II) was added to this liquid substrate at 0-1% w/w and dissolved by vacuum or without vacuum with low shear mixing. To make a more liquid substrate, 25-40% w/w of polyethylene glycol 4000 and 50-70% of polyethylene glycol 400, 0-10% stearyl alcohol and having a pair of 0-0.2% 6-25% water combination of methyl paraben.

Example 17. Non-clinical model of psoriasis in mice

Induction of psoriasis-like lesions is achieved in the BK5.Stat3C gene-transferred mouse model, in which constitutive activation of STAT3 in basal keratinocytes tends to develop spontaneous chronic dry sputum-like lesions at the tail end and in the gel A dry-like lesion was induced after stripping, trauma, or administration of 12-O-tetradecylidene phorbol-13-acetate (TPA). In this mode, adult mouse BK5.Stat3C is stripped on the shaved skin of the spine to induce dry lesions.

Each group of 5 BK5.Stat3C gene-transferred mice was treated with vehicle or daily oral administration of 1, 5 and 25 mg of the formula (II) / kg for 5 days. Positive control treatment was also given. The development of psoriasis lesions in the tape stripping area was assessed by clinical and histological scores. Briefly, acanthosis, vascular distribution, Ki67 performance, and infiltration of CD3 ⁺ T cells were scored microscopically. Additional markers of inflammation include immunohistochemical or flow cytometry analysis of dermal and epidermal immunoexudates of characteristic immune cell subsets, activated mast cells, neutrophils and Extracellular network. Acute lesions were assessed on day 5 of treatment. Spontaneous end-stage disease skin was assessed after 1, 2, and 4 weeks of dose administration in adult rats. Targeted array (ie, inflammation signature) in the psoriasis skin of BK5.Stat3C gene-transferred mice in mice treated with vehicle, positive control and formula (II) or Gene expression analysis of RNAseq to assess changes in the performance of cytokines, chemokines, and other mechanism markers of inflammation. The BTK target saturation associated with each dose value of formula (II) was measured in spleen cell preparations as well as in dermal exudates isolated from psoriasis and disease free skin. Alternatively, this mode can be carried out using a topical formulation of formula (II), which is administered directly to the tape stripped skin for assessing the efficacy of the early stages of psoriasis development or spontaneously occurring in BK5. The dry-like skin associated with chronic tail lesions in Stat3C gene-transferred mice.

Another mouse model of psoriasis involves transplantation of human xenografts from psoriasis into the dorsal skin of SCID mice (also known as Hu-SCID psoriasis mode) to allow for the systematic evaluation of experimental therapeutics. The Hu-SCID psoriasis pattern may require activated human T cells to be infused into mice to induce or maintain an autoimmune response within the plaque, whereas the xenograft skin is weak due to the presence of NK cells in SCID mice. Survive. Use of AGR129 mice (lacking IFN-α, IFN-β, and RAG-2) allows for the development of fully developed psoriasis phenotypes from pre-lesioned skin (based only on cells in the xenograft) within 6-8 weeks Do not use extra donor T cell stimulators. AGR129 mice from pre-lesioned skin xenografts from psoriasis patients can be treated as a treatment modality during the induction period or after establishing a dry sputum-like lesion in the allograft.

To assess the dose response and potency of formula (II), a daily dose of 1, 5 or 25 mg/kg administered orally is compared to a vehicle control and an active immunosuppressive agent (eg, an anti-TNF-α antibody). . The clinical characteristics of the plaque are scored weekly using a standardized scale of disease severity during the lifetime. The histopathological properties of allografts are assessed microscopically, including acanthosis, development of reticular sputum, dermal and lymphoid aggregates, inflammatory exudates, keratinocyte growth and differentiation of epidermal markers (eg Ki67, K16) , K17, nuclear enrichment and S100) and markers of infiltrating bone marrow cells (including mast cells, myeloid and plasmacytoid dendritic cells, macrophages, and neutrophils). Gene expression analysis of allografts before and after treatment can be used to assess the activation status of infiltrating cells, proinflammatory mediators The performance of substances and antimicrobial peptides. Alternatively, this mode can be carried out using a topical formulation of formula (II) that is administered directly to the allograft during the disease-inducing phase or after the development of the dry-like lesion.

Example 18. Non-clinical model of scleroderma in mice

Induction of scleroderma (or systemic sclerosis, SSc) can be assessed in a mouse model, including genetic patterns (ie, tight skin mice, TSK/+) and bleomycin-induced dermal fibrosis patterns. To assess the effect of formula (II) in a mouse model of scleroderma, 6-8 week old C3H/HeJ female mice were injected subcutaneously with bleomycin solution at selected ridge positions once every other day. After 4 weeks. During the induction period, the vehicle or formula (II) is administered orally orally at a dose of 1, 5 or 25 mg/kg. Mice were euthanized and removed from the skin of the spine, fixed in 10% neutral buffered formalin and paraffin embedded, and histologically evaluated by histochemical fibrosis and quantitative dermal thickness analysis. Myofibroblastic cell lines were identified by immunohistochemical staining of α-smooth muscle actin. Dermal exudates, immune complex formation and proliferation indices are measured by methods known to those skilled in the art. Each treatment group used for statistical evaluation of histopathological scores included 10 mice. The peripheral blood cytokine profile was assessed using a bead-based multiple ligand binding assay. In a subpopulation of samples, FFPE sections were submitted to quantitative mRNA analysis of in situ hybridization to assess the progenic fibrogenic cytokine profile (IL-6, TGF-[beta]) in the diseased skin.

Example 19. Non-clinical model of atopic dermatitis in mice and dogs

Skin phenotypes and pruritus associated with atopic dermatitis (AD) can be induced by exposure to specific pathogens and mice induced by antigenic stimuli such as Dust extract or trinitrochlorobenzene. Specific strains are modeled (with or without skin rupture). Under non-SPF (no specific pathogen) conditions, NC/Nga mice are susceptible to dermatitis and develop AD phenotypes with tape stripping and/or epidermal stimuli, even in cleaner facilities. Clinical and biochemical signs include erythema, edema, hyperplasia, hemorrhage, scarring, and epidermal shedding/erosion of inflammatory skin phenotypes with increased IL-5, IL-13, TARC, C-TACK, and eosin properties, Dermal accumulation of lymphocytes and mast cells, epidermal migration of neutrophils, neurite outgrowth, hyperplasia, acanthosis, deepened reticular sputum, and enrichment in lymphocytes and eosinophils Inflammatory exudate of the dermis.

These phenotypic changes in mice can be monitored clinically and histopathologically. The agent can be tested in NC/Nga mice and the total score is assessed by the histopathological properties of the disease. Additional quantitative data can be obtained from pressure-related analysis of actions related to itching and/or cage motion. Simultaneous observation of circulating Th2 and CLA ⁺ T cells, serum levels of IL-5, IL-13, TARC and eosin, specific receptors (such as PAR in the dermis and/or epidermis) -2, IL-31R, FcεR1), and an increase in the number of skin eosinophils and mast cells.

For example, NC/Nga mice are tape stripped and induced with Df antigen and administered as formula (II) when a moderate disease score is reached (eg, up to 3 points on a 4 point clinical rating scale). Start treatment on a rotating basis from 5-10 doses of vehicle control, from 5 mg/ml to 50 g/m A combination of formula (II) or a positive control dose of the ascending dose develops a sufficiently high clinical score with the aged rat. The improvement in pruritus is a strong clinical efficacy indicator in the mouse model, and additional mechanism messages are derived from the histological and molecular analysis of the affected skin. The manifestations of neuroinflammatory mediators (including IL-31, PAR-2, and substance P) and effects on pruroceptors, synaptic exogenous and dermal exudates can be performed using immunohistochemistry, in situ hybridization, or Evaluation of gene expression arrays.

Dogs with pruritic eczema are usually sedatives and/or topical corticosteroids or oral glucocorticoids for acute outbreaks and glucocorticoids, cyclosporine for chronic atopic dermatitis Treatment with antibodies or antifungal agents. Combination of antihistamine and oral glucocorticoid improves pruritus control, whereas antihistamine alone is insufficient to control atopic disease despite the presence of IgE and activation of dermal mast cells in affected skin .

In dogs with acute outbreaks of AD or chronic AD, the treatment of formula (II) is administered daily at a dose of 2.5 to 30 mg/kg. Capsules are administered daily, and the percentage of skin involvement, the disease and grade present on the paws, ears, and underarms, and the subjective score of the owner's itching behavior (ie, Visual Analogue Scale, VAS) The clinical characteristics of the disease were assessed weekly after baseline assessment. A psiesometry device can be placed on the dog's front or hind paw as an option to quantitatively assess the percentage of time that is busy with scratching. Histological examination of the affected skin was performed at baseline and at weeks 2, 4, and 12. All quantitative and qualitative measures of disease activity from dogs treated with formula (II) Assessment at baseline and at weeks 2, 4, and 12; treatment of formula (II) may be extended by the host's choice to up to 26 weeks in the responding animal. Clinical evaluation included the owner's VAS, the estimated percentage of affected body surface area, the severity of skin lesions, the presence and number of epidermal shedding, the affected paws and ears, and the composite score. Biomarkers from biopsies of affected skin relative to lesion-free skin locations were assessed to determine the degree of biological response, including serum chemistry, serum IgE levels, serum cytokines and chemokines, circulating bone marrow and lymphoid cells. Group, circulating CLA + lymphocytes and histopathology scores. Dogs were treated for up to 12 weeks and treated 4 weeks after stopping treatment. If efficacy is observed in dogs with more than one dose value, it may be worthwhile to choose to further evaluate the dose of formula (II) for additional studies. The dog can be orally treated with a liquid formulation of a capsule, a lozenge or a tube of the formula (II). Alternatively, Formula (II) can be formulated as described in Example 16 and topically administered to the affected area of the skin to treat acute AD, and/or in combination with short-term antimicrobial or antifungal therapies to treat the companion dog. Chronic AD.

Example 20. Non-clinical pattern of cutaneous lupus erythematosus in mice

Skin phenotypes associated with systemic lupus erythematosus and discoid lupus can be modeled using specific strains of mice. In lupus patients, the combination of congenital and strained immune responses to disorders and epidermal barrier disruption, sensitivity to mild skin damage and UV radiation causes skin characterization of erythema and disease. The production of antimicrobial peptides, cytokines, activation of keratinocytes via TLR or UV media, and activation of dermal plasmacytoid dendritic cells can also lead to increased systemic autoimmune reactivity and disease outbreaks. NZB x NZW (NZBW) F1 mice are preclinical models for the development and treatment of systemic and cutaneous lupus erythematosus. When proteinuria and/or serum urea nitrogen showed a disease onset, 11 week old NZBW F1 female mice had aged until 15-20 weeks. The skin of the back of the mouse was then shaved twice a week and exposed to 500 mJ/cm 2 of UVB light in a light-illuminated cage every other day for 8 weeks. Then, treatment with formula (II) was started, and 0, 1, 5 or 25 mg of formula (II) / kg was administered by oral administration once a day during the experiment. Alternatively, prevention of skin bursts can be assessed by treatment with formula (II) once daily by oral administration during light induction. The skin was scored twice a week with skin characterization of the disease. At the end of the treatment period, the mice were euthanized, and shaved and removed for histopathological evaluation, in situ or gelatinin electrophoresis, gene expression analysis, flow cytometry of the resident lymphocytes, and in the dermis The characteristics of the immune complex at the epidermal junction are deposited on the skin of the spine. Immuno-fluorescence techniques can be used for freeze-embedded or formalin-fixed paraffin-embedded skin samples from controls and treated NZBW mice. Therapeutic effects on subcutaneous edema, inflammatory cell exudates, and parakeratosis can be assessed in a semi-quantitative manner or by means of an image analysis system. At the time of sacrifice, plasma evaluation of BUN/creatinine, cytokines/chemokines, immunoglobulins, and specific autoantibodies (including ssDNA, dsDNA, and other autoimmune markers) can be performed. Renal histopathology can also be assessed to produce a systemic disease score.

Tape stripping of MLR/lpr mice also produces skin lesions associated with systemic effects, such as increased proteinuria. Therefore, skin characterization of systemic diseases can be induced in the mouse strain by destruction of the epidermal barrier hair. A similar study can be performed in formula (II) to assess the therapeutic effect during the induction interval or after clinical induction. Clinical, histopathological, and biochemical (serum) characterization of the disease in these lupus-susceptible mice can be scored as described above.

Claims (85)

A use of a Bruton's tyrosine kinase (BTK) inhibitor for the manufacture of a medicament or kit for treating a BTK-mediated disease in a human body, the treatment comprising the steps of: a) administering a first dose of a BTK inhibitor sufficient to provide the target BTK in the tissue chamber during the first period; and (b) administering a second dose of the BTK inhibitor during the second period, wherein the second dose is less The target BTK occupancy is provided at the first dose and sufficient to provide the target BTK in the tissue chamber. The use according to claim 1, wherein the target BTK occupant is selected from the group consisting of: greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, More than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%. The use according to the first aspect of the patent application, wherein the BTK occupation is estimated by a rate of BTK resynthesis in a tumor lesion or a disease site. The use according to claim 1, wherein the BTK occupation is estimated from a metabolic activity profile or a proliferation index in a tumor lesion or disease site. The use according to item 4 of the scope of the patent application, wherein the metabolically active profile is measured using a method selected from the group consisting of magnetic resonance imaging and positron emission tomography. The use according to the first aspect of the patent application, wherein the BTK occupation is evaluated based on a combination of BTK probes that bind to unoccupied BTK in a tumor lesion or disease site. The use according to claim 6 wherein the BTK probe is selected from the group consisting of a fluorescent probe and a positron emission tomography probe. According to the use of the first aspect of the patent application, wherein the BTK occupation is evaluated based on the average BTK resynthesis rate of a patient population suffering from a disease of the BTK vector. The use according to any one of claims 1 to 8, wherein the tissue compartment is selected from the group consisting of peripheral blood B cells, bone marrow B cells, lymph node B cells, autoreactive B cells, Plasma cells, regulatory B cells, follicular dendritic cells, dendritic cells derived from bone marrow, tumor stroma, tumor-associated macrophages, mast cells, alveolar macrophages, dust cells, plasmacytoid dendrites Cells, epidermal lymphocyte antigen (CLA)-positive T cells, lymphoid cells, Langerhans cells, mononuclear cells, macrophages, histiocytes, Kupffer cells, glial cells, microglia, Schwann cells, Ito cells, liver Stellate cells, pancreatic stellate cells, glioma cells, malignant B cells, fat cells, neutrophils, granules, neutrophils, eosinophils, hematopoietic stem cells, serous cells, mesenchymal cells, osteoblasts , osteoclasts, infiltrating lymphocytes, immune cells, and inflammatory exudates. The use according to any one of claims 1 to 8, wherein the tissue compartment is selected from the group consisting of peripheral blood, bone marrow, germinal center, lymphoid follicles, lymphoid tissue associated with the intestine, almond Gland, GALT, lymphoma lesions, ectopic lymphoid tissue, ectopic node, lymph node lesions, lymphadenopathy, spleen, solid tumor, tumor microenvironment, swollen Tumor matrix, bone, bone lesions, bone metastases, synovial fluid, articular surface, joints, kidney, liver, lung, branch tubules / bronchioles, mediastinum, pleura, peritoneum, cystadenocarcinoma, heart, pancreas, sinusoids, Eye, nerve, brain, brain metastasis, brain lesions, central nervous system, skin, stomach, lamina propria, intestinal tract, colon, exocrine gland, salivary gland, lacrimal gland, breast, dermis, subcutaneous tissue, epidermis, perivascular, inflammatory lesions, Granuloma, mast cell tumor, papule, testicle, ovary and bladder. The use according to any one of claims 1 to 8, wherein the BTK inhibitor is selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof. The use according to any one of claims 1 to 8 wherein the treatment further comprises the step of determining the target BTK occupancy in the tissue chamber using a relative resynthesis rate. The use according to any one of claims 1 to 8, wherein the first dose of the BTK inhibitor is administered once a day. The use according to any one of claims 1 to 8, wherein the first dose of the BTK inhibitor is administered twice daily. The use according to any one of claims 1 to 8, wherein the first dose of the BTK inhibitor is administered three times a day. The use according to any one of claims 1 to 8, wherein the second dose of the BTK inhibitor is administered once a day. The use according to any one of claims 1 to 8, wherein the second dose of the BTK inhibitor is administered twice daily. According to the use of any one of claims 1 to 8, Wherein the second dose of the BTK inhibitor is administered three times a day. The use according to any one of claims 1 to 8, wherein the first dose of the BTK inhibitor is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg . The use according to any one of claims 1 to 8, wherein the second dose of the BTK inhibitor is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg . The use according to any one of claims 1 to 8, wherein the first period is selected from the group consisting of: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days 8, 8, 9, 10, 11, 12, 13, 14, 14, 15, 16, 17, 18, 19, 20, and 21 days. The use according to any one of claims 1 to 8, wherein the second period is selected from the group consisting of: 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years and 10 years. The use according to any one of claims 1 to 8, wherein the first dose of the BTK inhibitor is administered orally. The use according to any one of claims 1 to 8, wherein the first dose of the BTK inhibitor is administered topically. The use according to any one of claims 1 to 8, wherein the second dose of the BTK inhibitor is administered orally. The use according to any one of claims 1 to 8, wherein the second dose of the BTK inhibitor is administered topically. The use according to any one of claims 1 to 8, wherein the BTK-mediated disease is a cancer selected from the group consisting of: Hodgkin's lymphoma, acute myeloid leukemia , chronic lymphocytic leukemia, small lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, MALT lymphoma, Waldenström's macroglobulinemia, follicular lymphoma , B cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile bone marrow monocystic leukemia, anterior lymphocytic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple Myeloma, thymoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin cancer, melanoma, eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, bladder cancer, Gastric cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head cancer, neck cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, Cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system cancer, acquired immunodeficiency syndrome-associated cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary Exudative lymphoma, adenoid cystic carcinoma, hepatocellular carcinoma, T-cell leukemia, and mastocytosis. The use according to any one of claims 1 to 8, wherein the BTK-mediated disease is an inflammatory, immunological or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic Inflammatory diseases, rheumatoid arthritis, osteoarthritis, osteoporosis, atherosclerosis, inflammatory bowel disease, skin diseases (such as cowhide) 癣, eczema and scleroderma), systemic sclerosis, diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, cystitis, vertebral Arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, suppurative sweat gland , Sjögren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis and true erythrocytosis. The use according to any one of claims 1 to 8, wherein the BTK-mediated disease is an immune rejection associated with organ or cell transplantation selected from the group consisting of: anti-allogeneic antibodies a condition, a condition associated with allograft rejection before, during or after organ or cell transplantation, a pre-transplant conditioning of a patient undergoing a solid organ transplant, a condition associated with acute humoral rejection, a condition associated with a heart transplant, Conditions associated with kidney transplantation, conditions associated with kidney transplantation, conditions associated with lung transplantation, conditions associated with liver transplantation, conditions associated with transplantation compatible with ABO, and conditions associated with stem cell transplantation. The use according to any one of claims 1 to 8, wherein the BTK-mediated disease is graft-versus-host disease (GVHD), wherein the GVHD is selected from the group consisting of: related to stem cell transplantation GVHD, GVHD associated with bone marrow transplantation, thymus GVHD, skin GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and slow Sexual GVHD. The use according to any one of claims 1 to 8, wherein the BTK-mediated disease is a skin disease, wherein the skin disease is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, red Psychotic psoriasis, nail sputum, pustular ring psoriasis, pustular psoriasis, reversal psoriasis, psoriatic arthritis, pus keratosis, psoriasis, nodular erythema, sweat glands of the hands and feet, Atopic dermatitis, atopic eczema, liposuction eczema, liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid erythema Lupus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, erythema multiforme, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, vulgaris Pemphigus, vesicular pemphigus, erythematous pemphigus, nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, whole body Scleroderma Characterization, diffuse cutaneous mastocytosis, erythrodermic mastocytosis, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, eosinophilic Dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like pimples pimples (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis - Herbmann disease (febrile ulceronecrotic) Mucha-Habermann disease) (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft versus host disease, cryoglobulin purpura and hyperglobulinemia purpura. According to the use of any one of claims 1 to 8, Wherein the BTK-mediated disease is a skin disease, wherein the skin disease results from a systemic disease in which sensitivity, lymphocyte recruitment, lymphocyte skewing of cells present by local or lymph node antigens, skin persistence or skin Homing lymphocyte activation, innate immune sensing, keratinocyte anti-microbial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils Skin characterization at the ball and/or Langerhans cells, and wherein the skin disease causes the development of skin lesions. The use according to any one of claims 1 to 8, wherein the diagnostic tool is used to assess BTK performance and/or resynthesis in the BTK vector disease, thereby determining an optimal treatment configuration for the BTK inhibitor . According to the use of claim 33, wherein the evaluation of BTK performance and/or resynthesis occurs prior to treatment of the BTK-mediated disease. According to the use of claim 33, wherein the evaluation of BTK performance and/or resynthesis occurs during the treatment of the BTK-mediated disease. According to the use of claim 33, wherein the assessment of BTK performance and/or resynthesis is used to identify patients who are likely to benefit from the treatment of formula (II). According to the use of claim 33, wherein the assessment of BTK performance and/or resynthesis is used to identify patients who are unlikely to benefit from the treatment of formula (II). According to the use of claim 33, wherein the evaluation of BTK performance and/or resynthesis is carried out using a pharmacodynamic extension of BTK pathway members or BTK pathway activation. According to the use of the scope of claim 33, wherein the diagnostic tool is a kit. According to the use of the scope of claim 33, wherein the diagnostic tool is a laboratory development test. A compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof for use in the manufacture of a medicament for the treatment of a condition in a human body, wherein the compound or a pharmaceutically acceptable salt thereof The crystal, hydrate, solvate or prodrug is administered at a dose selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg and 25 mg, wherein the dose is administered once a day. Twice a day or three times a day, and the dose is administered by a route of administration selected from the group consisting of oral administration, topical administration, and combinations thereof. The use according to claim 41, wherein the condition is cancer, and wherein the cancer is selected from the group consisting of non-Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, small Lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic leukemia, Burkitt's leukemia Juvenile bone marrow monocytic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin cancer, Melanoma, eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, adenoid cystic carcinoma, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer ), head cancer, neck cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system Cancer, acquired immunodeficiency syndrome-associated cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary exudative lymphoma, hepatocellular carcinoma, T-cell leukemia, and mastocytosis . The use according to claim 41, wherein the condition is an inflammatory, immune or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, Atherosclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, ulcer Colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile-type hair Arthritis, suppurative sweat gland inflammation, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis and true erythrocytosis. The use according to claim 41, wherein the condition is an immune rejection associated with organ or cell transplantation selected from the group consisting of: an anti-allogeneic antibody-related disorder, before or during an organ or cell transplantation Or subsequent conditions associated with allograft rejection, pre-transplant conditioning for patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, conditions associated with heart transplantation, conditions associated with kidney transplantation, and kidney Transplant-related disorders, disorders associated with lung transplantation, disorders associated with liver transplantation, disorders associated with ABO incompatible transplantation, and disorders associated with stem cell transplantation. The use according to claim 41, wherein the condition is graft versus host disease (GVHD), wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation, GVHD associated with bone marrow transplantation, Thymus GVHD, skin GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and chronic GVHD. The use according to claim 41, wherein the condition is a skin disease, wherein the skin disease is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythroderma psoriasis, nail sputum, pustules Sexual psoriasis, pustular psoriasis, inverted psoriasis, psoriasis Arthritis, septic skin keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, liposuction eczema, liposuction dermatitis, sweat blister Rash, rose spot, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, erythema multiforme, sputum, warts Lupus erythematosus, leukoplakia, alopecia areata, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus, nodular pemphigoid, red Dermatological sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse cutaneous mastocytosis, erythrodermic mastocytosis, ring granulation Swollen, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, eosinophilic dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like pimples Rash (PLEVA), chronic mossy sputum Rash (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft-versus-host disease, cryoglobulin purpura and high Globocytosis purpura. The use according to claim 41, wherein the condition is a skin disease, wherein the skin disease is caused by a systemic disease in which sensitivity, lymphatic recruitment, lymphocyte degeneration of cells presented by local or lymph node antigens, skin persistence or skin Homing lymphocyte activation, innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils and/ Or skin characterization at Langerhans cells, and wherein the skin disease causes skin The development of the lesion. The use according to any one of claims 41 to 47, wherein the human body is a member of a particular group. According to the use of the 48th scope of the patent application, the specific group may be selected from the following groups: children, adolescents, infants, adolescents, lactating mothers, pregnant women, elderly/weak individuals, and multiple medications. Patients, patients with liver damage, individuals with slow or intolerant and/or sensitive metabolism. A use of a BTK inhibitor for the manufacture of a medicament for the treatment of a BTK-mediated disease in a human body, the treatment comprising the steps of: administering a target BTK sufficient to provide a target in the tissue chamber during a second or long-term administration period Occupied doses and time course of BTK inhibitors. According to the use of claim 50, wherein the BTK-mediated disease is a cancer selected from the group consisting of: Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia , small lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic leukemia, Burkitt Leukemia, juvenile myelomonocytic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin Cancer, melanoma, eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, adenoid cystic carcinoma, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, milk Cancer, cervical cancer, head cancer, neck cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer , central nervous system cancer, acquired immunodeficiency syndrome-associated cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, and primary exudative lymphoma, hepatocellular carcinoma, T-cell leukemia, and hypertrophy Cytomegaly. The use according to claim 50, wherein the BTK-mediated disease is an inflammatory, immunological or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid Arthritis, atherosclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, Ulcerative colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile type Arthritis, suppurative sweat gland inflammation, Suge's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis and true erythrocytosis . The use according to claim 50, wherein the BTK-mediated disease is an immune rejection associated with organ or cell transplantation selected from the group consisting of: an anti-allogeneic antibody-related disorder, an organ or a cell Pre-transplantation-related disorders before, during, or after transplantation, pre-transplant conditioning in patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, heart transplant-related disorders, and kidney Transplant-related disorders, conditions associated with kidney transplantation, conditions associated with lung transplantation, conditions associated with liver transplantation, conditions associated with transplantation compatible with ABO, and conditions associated with stem cell transplantation. According to the use of claim 50, wherein the BTK-mediated disease is graft-versus-host disease (GVHD), wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation, and bone marrow transplantation. Related GVHD, thymus GVHD, cutaneous GVHD, gastrointestinal GVHD, liver GVHD, acute GVHD, and chronic GVHD. According to the use of claim 50, wherein the BTK-mediated disease is a skin disease, wherein the skin disease is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythroderma psoriasis, Cognac, pustular ring psoriasis, pustular psoriasis, reversal psoriasis, psoriatic arthritis, pussy keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, Atopic eczema, liposuction eczema, liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus , lupus nephritis, lupus erythematosus, erythema multiforme, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, large blisters Skin characterization of pemphigus, erythematous pemphigus, nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, systemic sclerosis Mi Cutaneous mastocytosis, erythrodermic mastocytosis, granuloma annulare, cartilage nodules dermatitis, contact dermatitis, drug rash, linear IgA bullous skin Skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like pimples pimples (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis - Herberman's disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft versus host disease, cryoglobulin purpura and hyperglobulinemia purpura. According to the use of the scope of claim 50, the disease caused by the BTK medium is a skin disease caused by a systemic disease in which the lymphatic ball is recruited, the lymphocytes are recruited by the local or lymph node antigen, and the skin is long. Lymphocyte activation in resident or skin homing, innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils Skin characterization at the ball and/or Langerhans cells, and wherein the skin disease causes the development of skin lesions. The use according to any one of claims 50 to 56, wherein the treated human body is part of a specific group. According to the use of the 57th scope of the patent application, the specific group may be selected from the following groups: children, adolescents, infants, adolescents, lactating mothers, pregnant women, elderly/weak individuals, and multiple medications. Patients, patients with liver damage, individuals with slow or intolerant and/or sensitive metabolism. The use according to any one of claims 50 to 56, wherein the target BTK occupancy is selected from the group consisting of: greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93 %, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and More than 99%. The use according to any one of claims 50 to 56, wherein the tissue compartment is selected from the group consisting of peripheral blood B cells, bone marrow B cells, lymph node B cells, autoreactive B cells, Plasma cells, regulatory B cells, follicular dendritic cells, dendritic cells derived from bone marrow, tumor stroma, tumor-associated macrophages, mast cells, alveolar macrophages, dust cells, plasmacytoid dendrites Cells, epidermal lymphocyte antigen (CLA)-positive T cells, lymphoid cells, Langerhans cells, mononuclear cells, macrophages, histiocytes, Kupffer cells, glial cells, microglia, Schwann cells, Ito cells, liver Stellate cells, pancreatic stellate cells, glioma cells, malignant B cells, fat cells, neutrophils, granules, neutrophils, eosinophils, hematopoietic stem cells, serous cells, mesenchymal cells, osteoblasts , osteoclasts, infiltrating lymphocytes, immune cells, and inflammatory exudates. The use according to any one of claims 50 to 56, wherein the tissue compartment is selected from the group consisting of peripheral blood, bone marrow, germinal center, lymphoid follicles, lymphoid tissue associated with the intestine, almond Gland, GALT, lymphoma lesions, ectopic lymphoid tissue, ectopic node, lymph node lesions, lymphadenopathy, spleen, solid tumor, tumor microenvironment, tumor stroma, bone, bone lesion, bone metastasis, synovial fluid, articular surface , joints, kidneys, liver, lungs, branches/bronchus, mediastinum, pleura, peritoneum, cystadenocarcinoma, heart, pancreas, sinusoids, eyes, nerves, brain, brain metastasis, brain lesions, central nervous system, skin , stomach, solid Layers, intestines, colon, exocrine glands, salivary glands, lacrimal glands, breast, dermis, subcutaneous tissue, epidermis, perivascular, inflammatory lesions, granuloma, mastocytoma, papules, testicles, ovaries and bladder. A use of a BTK inhibitor for the manufacture of a medicament for the treatment of a human BTK-mediated disease, the treatment comprising the steps of: administering a BTK inhibitor of a dosage form that provides controlled release of a BTK inhibitor over time, wherein This release is sufficient to provide target BTK occupancy in the tissue chamber during the second or long term administration period. The use according to the scope of claim 62, wherein the BTK-mediated disease is a cancer selected from the group consisting of non-Hodgkin's lymphoma, acute myeloid leukemia, chronic lymphocytic leukemia, small lymphoid Spheroid leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, B-cell acute lymphoblastic leukemia, Burkitt's leukemia, Juvenile bone marrow monocytic leukemia, mast cell leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, thymic carcinoma, brain cancer, glioma, lung cancer, squamous cell carcinoma, skin cancer, melanin Tumor, eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, adenoid cystic carcinoma, bladder cancer, stomach cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer (cervical cancer) , head cancer, neck cancer, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, central nervous system , Acquired immune deficiency syndrome-related cancers, cervical cancer (cervical carcinoma), nose Pharyngeal carcinoma, Kaposi's sarcoma, and primary exudative lymphoma, hepatocellular carcinoma, T-cell leukemia, and mastocytosis. The use according to the scope of claim 62, wherein the BTK-mediated disease is an inflammatory, immunological or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid Arthritis, atherosclerosis, inflammatory bowel disease, skin diseases (such as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, ulcer Colitis, atopic dermatitis, cystitis, vertebral arthritis, uveitis, Behcet's disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile-type hair Arthritis, suppurative sweat gland inflammation, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, asthma, Crohn's disease, lupus, lupus nephritis and true erythrocytosis. The use according to claim 62, wherein the BTK-mediated disease is an immune rejection associated with organ or cell transplantation selected from the group consisting of: an anti-allogeneic antibody-related disorder, an organ or a cell Pre-, all-transplant rejection, pre-transplant conditioning for patients undergoing solid organ transplantation, conditions associated with acute humoral rejection, conditions associated with heart transplantation, and kidney transplantation before, during, or after transplantation Conditions, conditions associated with kidney transplantation, conditions associated with lung transplantation, conditions associated with liver transplantation, conditions associated with transplantation compatible with ABO, and conditions associated with stem cell transplantation. According to the use of the 62nd scope of the patent application, which is BTK The disease of the vector is graft versus host disease (GVHD), wherein the GVHD is selected from the group consisting of GVHD associated with stem cell transplantation, GVHD associated with bone marrow transplantation, thymus GVHD, skin GVHD, gastrointestinal GVHD, Liver GVHD, acute GVHD, and chronic GVHD. According to the use of the scope of claim 62, wherein the BTK-mediated disease is a skin disease, wherein the skin disease is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythroderma psoriasis, Cognac, pustular ring psoriasis, pustular psoriasis, reversal psoriasis, psoriatic arthritis, pussy keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, Atopic eczema, liposuction eczema, liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus , lupus nephritis, lupus erythematosus, erythema multiforme, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, large blisters Skin characterization of pemphigus, erythematous pemphigus, nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, systemic sclerosis Mi Sexual cutaneous mastocytosis, erythrodermic mastocytosis, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, Follicular keratosis, lymphoma-like papulosis, acute lichen-like pimples pimples (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic sputum Measles, rheumatoid neutrophilic dermatitis, graft-versus-host disease Skin characterization, cryoglobulin purpura and hyperglobulinemia purpura. According to the use of the scope of claim 62, wherein the BTK-mediated disease is a skin disease, wherein the skin disease is caused by a systemic disease in which the lymphocytes are recruited, the lymphocytes are recruited by local or lymph node antigens, and the skin is deviated. Lymphocyte activation, innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, hooliganism Skin characterization at the ball and/or Langerhans cells, and wherein the skin disease causes the development of skin lesions. The use according to any one of claims 62 to 68, wherein the treated human body is part of a specific group. According to the use of Article 69 of the scope of patent application, the specific group may be selected from the following groups: children, adolescents, infants, adolescents, lactating mothers, pregnant women, elderly/weak individuals, and multiple medications. Patients, patients with liver damage, individuals with slow or intolerant and/or sensitive metabolism. The use according to any one of claims 62 to 68, wherein the target BTK occupancy is selected from the group consisting of: greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93 %, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%. The use according to any one of claims 62 to 68, wherein the tissue compartment is selected from the group consisting of peripheral blood B cells, bone marrow B cells, lymph node B cells, autoreactive B fine Cells, plasma cells, regulatory B cells, follicular dendritic cells, dendritic cells derived from bone marrow, tumor stroma, tumor-associated macrophages, mast cells, alveolar macrophages, dust cells, plasmacytoids Dendritic cells, epidermal lymphocyte antigen (CLA)-positive T cells, lymphoid cells, Langerhans cells, mononuclear cells, macrophages, histiocytes, Kupffer cells, glial cells, microglia, Schwann cells, Ito cells Hepatic stellate cells, pancreatic stellate cells, glioma cells, malignant B cells, fat cells, neutrophils, granules, neutrophils, eosinophils, hematopoietic stem cells, serous cells, mesenchymal cells, Osteocytes, osteoclasts, infiltrating lymphocytes, immune cells, and inflammatory exudates. The use according to any one of claims 62 to 68, wherein the tissue compartment is selected from the group consisting of peripheral blood, bone marrow, germinal center, lymphoid follicles, lymphoid tissue associated with the intestine, almond Gland, lymphoma lesions, ectopic lymphoid tissue, ectopic node, lymph node lesions, lymphadenopathy, spleen, solid tumor, tumor microenvironment, tumor stroma, bone, bone lesion, bone metastasis, synovial fluid, articular surface, joint , kidney, liver, lung, branch tubule / bronchiole, mediastinum, pleura, peritoneum, cystadenocarcinoma, heart, pancreas, sinusoids, eye, nerve, brain, brain metastasis, brain lesions, central nervous system, skin, stomach , lamina propria, intestinal tube, colon, exocrine gland, salivary gland, lacrimal gland, breast, dermis, subcutaneous tissue, epidermis, perivascular, inflammatory lesions, granuloma, mast cell tumor, papule, testicular, ovary and bladder. A pharmaceutical composition comprising a compound selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 74, wherein the dosage is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. The pharmaceutical composition according to any one of claims 74 to 75, wherein the composition is suitable for local delivery. A pharmaceutical composition for use in the manufacture of a medicament according to any one of claims 74 to 76, which is for use in the treatment of a skin condition. The use according to claim 77, wherein the dermatological condition is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythroderma psoriasis, nail sputum, pustular ring psoriasis, pustules Psoriasis, reversal psoriasis, psoriatic arthritis, septic skin keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, liposuction eczema , liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, Pleomorphic erythema, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus , nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse skin mastocytosis, red skin disease Mast cell hypertrophy, ring granuloma, nodular cartilage dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, Acute moss-like pimples-like pityriasis (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer necrosis-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophil dermatitis , skin characterization of graft versus host disease, cryoglobulin purpura and hyperglobulinemia purpura. According to the use of claim 77, wherein the skin disease is caused by a systemic disease in which lymphocytes are recruited by sensitive lymphocytes, localized or lymph node antigen-presenting lymphocytes, local skin or skin homing, Skin characterization of innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans cells And wherein the skin disease causes the development of skin lesions. A use of a BTK inhibitor for the manufacture of a medicament for the treatment of a skin condition. According to the application of claim 80, wherein the dermatological condition is selected from the group consisting of psoriasis vulgaris, psoriasis psoriasis, erythrodermic psoriasis, nail sputum, pustular ring psoriasis, pustules Psoriasis, reversal psoriasis, psoriatic arthritis, septic skin keratosis, psoriasis, nodular erythema, hand and foot sweat gland inflammation, atopic dermatitis, atopic eczema, liposuction eczema , liposuction dermatitis, sweat herpes, rose plaque, cutaneous lupus erythematosus, acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, swollen lupus erythematosus, lupus nephritis, lupus erythematosus, Pleomorphic erythema, sputum, verrucous lupus erythematosus, leukoplakia, round baldness, nodular pruritus, lichen planus, pigmented pruritus, pemphigus vulgaris, vesicular pemphigus, erythematous pemphigus , nodular pemphigoid, erythrodermic sarcoidosis, vaginal dermatitis, scleroderma, systemic sclerosis, skin characterization of systemic sclerosis, diffuse skin mastocytosis, red skin disease Mastocytosis, granuloma annulare, cartilage nodules dermatitis, contact dermatitis, drug rash, linear IgA bullous skin disease, acidophilic dermatitis, follicular keratosis, lymphoma-like papulosis, acute lichen-like pityriasis pneumonia (PLEVA), chronic lichen-like pityriasis (PLC), febrile ulcer Necrotic wood-Herbman disease (FUMHD), chronic urticaria, rheumatoid neutrophilic dermatitis, skin characterization of graft-versus-host disease, cryoglobulin purpura and hyperglobulinemia purpura . According to the application of claim 80, wherein the skin disease is caused by a systemic disease in which lymphocytes are recruited by sensitivity, lymphatic recruitment, lymphocyte degeneration of cells present by local or lymph node antigens, skin standing or skin homing, Skin characterization of innate immune sensing, keratinocyte antimicrobial response, long-term or infiltrating bone marrow dendritic cell activation, plasmacytoid dendritic cells, macrophages, mast cells, neutrophils and/or Langerhans cells And wherein the skin disease causes the development of skin lesions. The use according to claim 80, wherein the dermatological condition is selected from the group consisting of psoriasis, scleroderma, atopic dermatitis and cutaneous lupus erythematosus. The use according to any one of claims 80 to 83, wherein the BTK inhibitor is selected from the group consisting of: Or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or prodrug thereof. The use according to any one of claims 80 to 83, wherein the therapeutically effective dose of the BTK inhibitor is selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg and 100 </ RTI> mg, wherein the therapeutically effective dose is administered at intervals selected from the group consisting of: once daily, twice daily, three times daily, and four times daily, and wherein the therapeutically effective dose is selected from the group consisting of Routes of group administration: oral administration, topical administration, and combinations thereof.